WO1992021360A1 - Derives substitues n-carboxyalkylpeptidyle en tant qu'agents antidegeneratifs - Google Patents
Derives substitues n-carboxyalkylpeptidyle en tant qu'agents antidegeneratifs Download PDFInfo
- Publication number
- WO1992021360A1 WO1992021360A1 PCT/US1992/003809 US9203809W WO9221360A1 WO 1992021360 A1 WO1992021360 A1 WO 1992021360A1 US 9203809 W US9203809 W US 9203809W WO 9221360 A1 WO9221360 A1 WO 9221360A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ethyl
- carboxy
- alkyl
- glycine
- phenyl
- Prior art date
Links
- 239000013543 active substance Substances 0.000 title description 3
- 230000001796 anti-degenerative effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 239000011159 matrix material Substances 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 230000001404 mediated effect Effects 0.000 claims abstract description 11
- -1 (2) naphthyl Chemical group 0.000 claims description 116
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 113
- 238000000034 method Methods 0.000 claims description 69
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 claims description 25
- 239000004471 Glycine Substances 0.000 claims description 24
- 150000002431 hydrogen Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000001041 indolyl group Chemical group 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 229940024606 amino acid Drugs 0.000 claims description 16
- 235000001014 amino acid Nutrition 0.000 claims description 16
- 150000001413 amino acids Chemical class 0.000 claims description 16
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- URDCUMNXFAPPEG-MGGUFVSOSA-N (2s)-2-amino-4-methylpentanoic acid;(2s)-2-[[(1r)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound CC(C)C[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 URDCUMNXFAPPEG-MGGUFVSOSA-N 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- 150000003951 lactams Chemical class 0.000 claims description 10
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 231100000252 nontoxic Toxicity 0.000 claims description 7
- 230000003000 nontoxic effect Effects 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
- 229960003104 ornithine Drugs 0.000 claims description 5
- NUXUIBNLDBQZLX-LFBMMIFQSA-N (2s)-2-amino-4-methylpentanoic acid;(2r)-2-[[(1s)-1-carboxy-3-phenylpropyl]amino]-6-(3-oxo-1h-isoindol-2-yl)hexanoic acid Chemical compound CC(C)C[C@H](N)C(O)=O.C([C@H](N[C@H](CCCCN1C(C2=CC=CC=C2C1)=O)C(=O)O)C(O)=O)CC1=CC=CC=C1 NUXUIBNLDBQZLX-LFBMMIFQSA-N 0.000 claims description 4
- UHGULLIUJBCTEF-UHFFFAOYSA-N 2-aminobenzothiazole Chemical compound C1=CC=C2SC(N)=NC2=C1 UHGULLIUJBCTEF-UHFFFAOYSA-N 0.000 claims description 4
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 claims description 4
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910052702 rhenium Inorganic materials 0.000 claims description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 3
- HKLDDHUTUSWPLP-GOVISYOBSA-N (2S)-2-[[(1R)-1-carboxyethyl]amino]-4-phenylbutanoic acid (2S)-2,4-diamino-4-oxobutanoic acid Chemical compound OC(=O)[C@@H](N)CC(N)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 HKLDDHUTUSWPLP-GOVISYOBSA-N 0.000 claims description 3
- IDIBYGCOINBFOQ-XRYPNNLHSA-N (2S)-2-amino-3-(1H-indol-3-yl)propanoic acid (2S)-2-[[(1R)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 IDIBYGCOINBFOQ-XRYPNNLHSA-N 0.000 claims description 3
- VNPOSNKLMDEAFM-JMNJYYLBSA-N (2S)-2-amino-3-methylbutanoic acid (2S)-2-[[(1R)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound CC(C)[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 VNPOSNKLMDEAFM-JMNJYYLBSA-N 0.000 claims description 3
- KSRLZFABNIEZLF-NWRCOATISA-N (2S)-2-amino-3-phenylpropanoic acid (2S)-2-[[(1R)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 KSRLZFABNIEZLF-NWRCOATISA-N 0.000 claims description 3
- WRKVTZFMNYDDEM-DGLLDHGFSA-N (2S)-2-amino-4-methylpentanoic acid (2R)-2-[[(1S)-1-carboxy-3-(4-propylphenyl)propyl]amino]-6-(3-oxo-1H-isoindol-2-yl)hexanoic acid Chemical compound CC(C)C[C@H](N)C(O)=O.C1=CC(CCC)=CC=C1CC[C@@H](C(O)=O)N[C@@H](C(O)=O)CCCCN1C(=O)C2=CC=CC=C2C1 WRKVTZFMNYDDEM-DGLLDHGFSA-N 0.000 claims description 3
- LCZFWDKKUOGSEQ-PRZZSCJQSA-N (2S)-2-amino-4-methylpentanoic acid (2S)-2-[[(1R)-1-carboxyethyl]amino]-4-(4-propylphenyl)butanoic acid Chemical compound CC(C)C[C@H](N)C(O)=O.CCCC1=CC=C(CC[C@H](N[C@H](C)C(O)=O)C(O)=O)C=C1 LCZFWDKKUOGSEQ-PRZZSCJQSA-N 0.000 claims description 3
- CNLQDGBEHUSSNX-GKRRINMQSA-N (2s)-2-amino-4-methylpentanoic acid;(2s)-2-[[(1r)-1-carboxyethyl]amino]-4-(4-methylphenyl)butanoic acid Chemical compound CC(C)C[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=C(C)C=C1 CNLQDGBEHUSSNX-GKRRINMQSA-N 0.000 claims description 3
- MSECZMWQBBVGEN-LURJTMIESA-N (2s)-2-azaniumyl-4-(1h-imidazol-5-yl)butanoate Chemical compound OC(=O)[C@@H](N)CCC1=CN=CN1 MSECZMWQBBVGEN-LURJTMIESA-N 0.000 claims description 3
- VGQHOKKMMWXFDO-BWKNIZILSA-N (2s,3r)-2-amino-3-hydroxybutanoic acid;(2s)-2-[[(1r)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound C[C@@H](O)[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 VGQHOKKMMWXFDO-BWKNIZILSA-N 0.000 claims description 3
- AGUMDJJFOUSSJU-DXQVBPQOSA-N (2s,3s)-2-amino-3-methylpentanoic acid;(2s)-2-[[(1r)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound CC[C@H](C)[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 AGUMDJJFOUSSJU-DXQVBPQOSA-N 0.000 claims description 3
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 3
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 claims description 3
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 3
- BNOWTNJJTBHENE-YIBYAYNTSA-N CC(C)C[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=C(Cl)C=C1 Chemical compound CC(C)C[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=C(Cl)C=C1 BNOWTNJJTBHENE-YIBYAYNTSA-N 0.000 claims description 3
- PSIKHXGPWFEDFB-GOVISYOBSA-N C[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 Chemical compound C[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 PSIKHXGPWFEDFB-GOVISYOBSA-N 0.000 claims description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 3
- LCWXJXMHJVIJFK-UHFFFAOYSA-N Hydroxylysine Natural products NCC(O)CC(N)CC(O)=O LCWXJXMHJVIJFK-UHFFFAOYSA-N 0.000 claims description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 3
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 claims description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims description 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 3
- 239000004473 Threonine Substances 0.000 claims description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 3
- 235000004279 alanine Nutrition 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 235000009582 asparagine Nutrition 0.000 claims description 3
- 229960001230 asparagine Drugs 0.000 claims description 3
- 229960005261 aspartic acid Drugs 0.000 claims description 3
- 235000003704 aspartic acid Nutrition 0.000 claims description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 3
- 235000013477 citrulline Nutrition 0.000 claims description 3
- 229960002173 citrulline Drugs 0.000 claims description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 claims description 3
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 claims description 3
- 235000013922 glutamic acid Nutrition 0.000 claims description 3
- 239000004220 glutamic acid Substances 0.000 claims description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 3
- QJHBJHUKURJDLG-UHFFFAOYSA-N hydroxy-L-lysine Natural products NCCCCC(NO)C(O)=O QJHBJHUKURJDLG-UHFFFAOYSA-N 0.000 claims description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 3
- 229960000310 isoleucine Drugs 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 3
- 229960004441 tyrosine Drugs 0.000 claims description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 3
- 239000004474 valine Substances 0.000 claims description 3
- LMSJDCZRVPZSDF-LCPQVDFXSA-N (2S)-2-amino-4-methylpentanoic acid (2R)-2-[[(1S)-1-carboxy-3-phenylpropyl]amino]-6-(1,3-dioxoisoindol-2-yl)hexanoic acid Chemical compound CC(C)C[C@H](N)C(O)=O.C([C@H](N[C@H](CCCCN1C(C2=CC=CC=C2C1=O)=O)C(=O)O)C(O)=O)CC1=CC=CC=C1 LMSJDCZRVPZSDF-LCPQVDFXSA-N 0.000 claims description 2
- VRWLUEHLLKKBPJ-IIKFGLAKSA-N (2S)-2-amino-4-methylpentanoic acid (2S)-2-[[(1R)-1-carboxyethyl]amino]-4-(4-ethylphenyl)butanoic acid Chemical compound CC(C)C[C@H](N)C(O)=O.CCC1=CC=C(CC[C@H](N[C@H](C)C(O)=O)C(O)=O)C=C1 VRWLUEHLLKKBPJ-IIKFGLAKSA-N 0.000 claims description 2
- HYTQXCIXKZKOSK-MGGUFVSOSA-N (2S)-2-aminohexanoic acid (2S)-2-[[(1R)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound CCCC[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 HYTQXCIXKZKOSK-MGGUFVSOSA-N 0.000 claims description 2
- MSLWAYFHHGWPBV-YIBYAYNTSA-N (2s)-2-amino-4-methylpentanoic acid;(2s)-2-[[(1r)-1-carboxyethyl]amino]-4-(3-hydroxyphenyl)butanoic acid Chemical compound CC(C)C[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC(O)=C1 MSLWAYFHHGWPBV-YIBYAYNTSA-N 0.000 claims description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 2
- NGFQXYLWQODUIL-UHFFFAOYSA-N cyclohexylazanide Chemical compound [NH-]C1CCCCC1 NGFQXYLWQODUIL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 2
- PCAJPMYGUAZSBL-DTTLSXIQSA-N (2S)-2-amino-5-(diaminomethylideneamino)pentanoic acid (2S)-2-[[(1R)-1-carboxyethyl]amino]-4-(4-propylphenyl)butanoic acid Chemical compound OC(=O)[C@@H](N)CCCNC(N)=N.CCCC1=CC=C(CC[C@H](N[C@H](C)C(O)=O)C(O)=O)C=C1 PCAJPMYGUAZSBL-DTTLSXIQSA-N 0.000 claims 1
- RMXHQRJWJYIQQK-SYCLBLQOSA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid;(2r)-2-[[(1s)-1-carboxy-3-phenylpropyl]amino]-6-(3-oxo-1h-isoindol-2-yl)hexanoic acid Chemical compound OC(=O)[C@@H](N)CCCNC(N)=N.C([C@H](N[C@H](CCCCN1C(C2=CC=CC=C2C1)=O)C(=O)O)C(O)=O)CC1=CC=CC=C1 RMXHQRJWJYIQQK-SYCLBLQOSA-N 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 claims 1
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 abstract description 43
- 108091007196 stromelysin Proteins 0.000 abstract description 38
- 102000029816 Collagenase Human genes 0.000 abstract description 30
- 108060005980 Collagenase Proteins 0.000 abstract description 30
- 229960002424 collagenase Drugs 0.000 abstract description 30
- 239000003112 inhibitor Substances 0.000 abstract description 18
- 102000013382 Gelatinases Human genes 0.000 abstract description 13
- 108010026132 Gelatinases Proteins 0.000 abstract description 13
- 102000003843 Metalloendopeptidases Human genes 0.000 abstract description 11
- 108090000131 Metalloendopeptidases Proteins 0.000 abstract description 11
- 210000001188 articular cartilage Anatomy 0.000 abstract description 8
- 208000037260 Atherosclerotic Plaque Diseases 0.000 abstract description 7
- 201000008482 osteoarthritis Diseases 0.000 abstract description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 7
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 206010011091 Coronary artery thrombosis Diseases 0.000 abstract description 5
- 102000035195 Peptidases Human genes 0.000 abstract description 5
- 108091005804 Peptidases Proteins 0.000 abstract description 5
- 206010064390 Tumour invasion Diseases 0.000 abstract description 5
- 210000002469 basement membrane Anatomy 0.000 abstract description 5
- 230000009400 cancer invasion Effects 0.000 abstract description 5
- 208000002528 coronary thrombosis Diseases 0.000 abstract description 5
- 206010053555 Arthritis bacterial Diseases 0.000 abstract description 4
- 208000004575 Infectious Arthritis Diseases 0.000 abstract description 4
- 238000002513 implantation Methods 0.000 abstract description 4
- 230000016087 ovulation Effects 0.000 abstract description 4
- 235000019833 protease Nutrition 0.000 abstract description 4
- 201000001223 septic arthritis Diseases 0.000 abstract description 4
- 206010014989 Epidermolysis bullosa Diseases 0.000 abstract description 3
- 206010064996 Ulcerative keratitis Diseases 0.000 abstract description 3
- 230000000593 degrading effect Effects 0.000 abstract description 3
- 208000028169 periodontal disease Diseases 0.000 abstract description 3
- 201000001474 proteinuria Diseases 0.000 abstract description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 2
- 208000014674 injury Diseases 0.000 abstract description 2
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 230000008736 traumatic injury Effects 0.000 abstract description 2
- 229910052725 zinc Inorganic materials 0.000 abstract description 2
- 239000011701 zinc Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 112
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- 239000000243 solution Substances 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
- 238000005481 NMR spectroscopy Methods 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 238000011282 treatment Methods 0.000 description 16
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 241000282414 Homo sapiens Species 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 229960001866 silicon dioxide Drugs 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- VKPSSPOUDYADLL-NSHDSACASA-N (2s)-4-oxo-4-(4-propylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]butanoic acid Chemical compound CCCC1=CC=C(C(=O)C[C@H](NC(=O)C(F)(F)F)C(O)=O)C=C1 VKPSSPOUDYADLL-NSHDSACASA-N 0.000 description 7
- 125000001931 aliphatic group Chemical group 0.000 description 7
- 150000003862 amino acid derivatives Chemical class 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- IFENLKSNCKYHMQ-SFHVURJKSA-N (2s)-4-(3,4-dimethylphenyl)-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound C1=C(C)C(C)=CC=C1CC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 IFENLKSNCKYHMQ-SFHVURJKSA-N 0.000 description 6
- UJQDHAGVQRYCFM-LBPRGKRZSA-N (2s)-4-(4-propylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]butanoic acid Chemical compound CCCC1=CC=C(CC[C@H](NC(=O)C(F)(F)F)C(O)=O)C=C1 UJQDHAGVQRYCFM-LBPRGKRZSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- 108010016626 Dipeptides Proteins 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 108010016160 Matrix Metalloproteinase 3 Proteins 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 210000002950 fibroblast Anatomy 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 210000000585 glomerular basement membrane Anatomy 0.000 description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 4
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 4
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 4
- 102000005741 Metalloproteases Human genes 0.000 description 4
- 108010006035 Metalloproteases Proteins 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 239000002442 collagenase inhibitor Substances 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 210000002808 connective tissue Anatomy 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000002797 proteolythic effect Effects 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- ULHDMLUUUQSHMK-KOLCDFICSA-N (2s)-2-[[(1r)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 ULHDMLUUUQSHMK-KOLCDFICSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 3
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 210000001612 chondrocyte Anatomy 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 210000004087 cornea Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 210000002744 extracellular matrix Anatomy 0.000 description 3
- 210000004195 gingiva Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 108010029690 procollagenase Proteins 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 235000006491 Acacia senegal Nutrition 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- NOWRHAGXISONBY-QWAZYABZSA-N CC(C)C[C@H](N)C(O)=O.C1=C(C)C(C)=CC=C1CC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 Chemical compound CC(C)C[C@H](N)C(O)=O.C1=C(C)C(C)=CC=C1CC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 NOWRHAGXISONBY-QWAZYABZSA-N 0.000 description 2
- RZOBHIALGLJUFD-FIZIFZEPSA-N CC(C)C[C@H](N)C(O)=O.CC1=CC=C(CC[C@H](N)C(O)=O)C=C1C Chemical compound CC(C)C[C@H](N)C(O)=O.CC1=CC=C(CC[C@H](N)C(O)=O)C=C1C RZOBHIALGLJUFD-FIZIFZEPSA-N 0.000 description 2
- SYHGXYHIODFHFM-OEFIRVHCSA-N CC(C)C[C@H](N)C(O)=O.CCCC1=CC=C(CC[C@H](N)C(O)=O)C=C1 Chemical compound CC(C)C[C@H](N)C(O)=O.CCCC1=CC=C(CC[C@H](N)C(O)=O)C=C1 SYHGXYHIODFHFM-OEFIRVHCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 108010062466 Enzyme Precursors Proteins 0.000 description 2
- 102000010911 Enzyme Precursors Human genes 0.000 description 2
- 208000022461 Glomerular disease Diseases 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 102000000424 Matrix Metalloproteinase 2 Human genes 0.000 description 2
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 241000219061 Rheum Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 210000002459 blastocyst Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 230000008355 cartilage degradation Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 235000013365 dairy product Nutrition 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 231100000852 glomerular disease Toxicity 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- KUHRIIPUCPOQMQ-UHFFFAOYSA-N n,n-diethyl-3-(ethyliminomethylideneamino)propan-1-amine Chemical compound CCN=C=NCCCN(CC)CC KUHRIIPUCPOQMQ-UHFFFAOYSA-N 0.000 description 2
- ABTJOHYOWBAGTP-REOHCLBHSA-N n-[(3s)-2,5-dioxooxolan-3-yl]-2,2,2-trifluoroacetamide Chemical compound FC(F)(F)C(=O)N[C@H]1CC(=O)OC1=O ABTJOHYOWBAGTP-REOHCLBHSA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 230000003239 periodontal effect Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 125000003395 phenylethylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- VCACNTQINXTXFY-GOVISYOBSA-N (2S)-2-amino-3-hydroxypropanoic acid (2S)-2-[[(1R)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound OC[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 VCACNTQINXTXFY-GOVISYOBSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- RWJUTJBZOSZXRM-QAPCUYQASA-N (2s)-2-[[(2r)-1-oxo-1-phenylmethoxypropan-2-yl]amino]-4-phenylbutanoic acid Chemical compound C([C@H](N[C@H](C)C(=O)OCC=1C=CC=CC=1)C(O)=O)CC1=CC=CC=C1 RWJUTJBZOSZXRM-QAPCUYQASA-N 0.000 description 1
- WNALLNDUPHTAEL-RRPNLBNLSA-N (2s)-2-[[(2r)-6-(1,3-dioxoisoindol-2-yl)-1-oxo-1-phenylmethoxyhexan-2-yl]amino]-4-phenylbutanoic acid Chemical compound C([C@@H](C(=O)O)N[C@H](CCCCN1C(C2=CC=CC=C2C1=O)=O)C(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WNALLNDUPHTAEL-RRPNLBNLSA-N 0.000 description 1
- JNJRVMLXHPUEMW-JMNJYYLBSA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid;(2s)-2-[[(1r)-1-carboxyethyl]amino]-4-phenylbutanoic acid Chemical compound OC(=O)[C@@H](N)CCCNC(N)=N.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 JNJRVMLXHPUEMW-JMNJYYLBSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- DANMWBNOPFBJSZ-UHFFFAOYSA-N 1-iodo-2,3-dimethylbenzene Chemical group CC1=CC=CC(I)=C1C DANMWBNOPFBJSZ-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 1
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- XMZQWZJMTBCUFT-UHFFFAOYSA-N 3-bromopropylbenzene Chemical compound BrCCCC1=CC=CC=C1 XMZQWZJMTBCUFT-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- CSFRCLYFVINMBZ-UHFFFAOYSA-N 4-iodo-1,2-dimethylbenzene Chemical compound CC1=CC=C(I)C=C1C CSFRCLYFVINMBZ-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- ZKRFOXLVOKTUTA-KQYNXXCUSA-N 9-(5-phosphoribofuranosyl)-6-mercaptopurine Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=S)=C2N=C1 ZKRFOXLVOKTUTA-KQYNXXCUSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- BUQICHWNXBIBOG-LMVFSUKVSA-N Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)N BUQICHWNXBIBOG-LMVFSUKVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 241001156002 Anthonomus pomorum Species 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- QUNMXHMJMXHNOL-GZXAFANHSA-N CC(C)C[C@H](N)C(O)=O.C([C@H](N[C@H](C)C(=O)OCC=1C=CC=CC=1)C(O)=O)CC1=CC=C(C)C(C)=C1 Chemical compound CC(C)C[C@H](N)C(O)=O.C([C@H](N[C@H](C)C(=O)OCC=1C=CC=CC=1)C(O)=O)CC1=CC=C(C)C(C)=C1 QUNMXHMJMXHNOL-GZXAFANHSA-N 0.000 description 1
- GNJNFATZFINQOS-JULVDDGKSA-N CC(C)C[C@H](N)C(O)=O.C1=CC(CCC)=CC=C1CC[C@@H](C(O)=O)N[C@H](C)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)C[C@H](N)C(O)=O.C1=CC(CCC)=CC=C1CC[C@@H](C(O)=O)N[C@H](C)C(=O)OCC1=CC=CC=C1 GNJNFATZFINQOS-JULVDDGKSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010007710 Cartilage injury Diseases 0.000 description 1
- 241000819038 Chichester Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000000503 Collagen Type II Human genes 0.000 description 1
- 108010041390 Collagen Type II Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 229940122858 Elastase inhibitor Drugs 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 101001013150 Homo sapiens Interstitial collagenase Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 108010042918 Integrin alpha5beta1 Proteins 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 108010028275 Leukocyte Elastase Proteins 0.000 description 1
- 102000016799 Leukocyte elastase Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 1
- PSYCEMCNUBJSQT-MGGUFVSOSA-N NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 Chemical compound NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](C)N[C@H](C(O)=O)CCC1=CC=CC=C1 PSYCEMCNUBJSQT-MGGUFVSOSA-N 0.000 description 1
- OEUPJXQVKDHCSS-YVQRCSLQSA-N N[C@@H](CC(C)C)C(=O)O.C(=O)(O)[C@@H](C)N[C@H](C(=O)O)CCC1=CC(=C(C=C1)C)C Chemical compound N[C@@H](CC(C)C)C(=O)O.C(=O)(O)[C@@H](C)N[C@H](C(=O)O)CCC1=CC(=C(C=C1)C)C OEUPJXQVKDHCSS-YVQRCSLQSA-N 0.000 description 1
- 229910020889 NaBH3 Inorganic materials 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 101000925883 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) Elastase Proteins 0.000 description 1
- 102000003743 Relaxin Human genes 0.000 description 1
- 108090000103 Relaxin Proteins 0.000 description 1
- 101710205657 Secreted proteinase Proteins 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 101000584292 Streptomyces cacaoi Mycolysin Proteins 0.000 description 1
- 102100030416 Stromelysin-1 Human genes 0.000 description 1
- 101710108790 Stromelysin-1 Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- BMINCTBIIZVJOR-XRVQSCEISA-N benzyl (2R)-2,6-diamino-6-(1,3-dioxoisoindol-2-yl)hexanoate hydrochloride Chemical compound C1=CC=C(C=C1)COC(=O)[C@@H](CCCC(N)N2C(=O)C3=CC=CC=C3C2=O)N.Cl BMINCTBIIZVJOR-XRVQSCEISA-N 0.000 description 1
- ZYTLPUIDJRKAAM-QMMMGPOBSA-N benzyl (2s)-2-hydroxypropanoate Chemical compound C[C@H](O)C(=O)OCC1=CC=CC=C1 ZYTLPUIDJRKAAM-QMMMGPOBSA-N 0.000 description 1
- CNNBRFOPQDCGFV-UHFFFAOYSA-N benzyl 2-oxopropanoate Chemical compound CC(=O)C(=O)OCC1=CC=CC=C1 CNNBRFOPQDCGFV-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000003366 colagenolytic effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009838 combustion analysis Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000003413 degradative effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002988 disease modifying antirheumatic drug Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000010318 early mammalian development Effects 0.000 description 1
- 239000003602 elastase inhibitor Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000001900 endoderm Anatomy 0.000 description 1
- 230000009088 enzymatic function Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000008175 fetal development Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000002406 gelatinase inhibitor Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000024693 gingival disease Diseases 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 210000002503 granulosa cell Anatomy 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 230000008407 joint function Effects 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229940127126 plasminogen activator Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridin-4-ylmethanol Chemical compound OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- SSNXHHIKGMYSIV-UHFFFAOYSA-N tert-butyl 2-oxo-4-phenylbutanoate Chemical compound CC(C)(C)OC(=O)C(=O)CCC1=CC=CC=C1 SSNXHHIKGMYSIV-UHFFFAOYSA-N 0.000 description 1
- PAGFOTUDGKPNMP-UHFFFAOYSA-N tert-butyl 4-(4-methylphenyl)-2-oxobutanoate Chemical compound CC1=CC=C(CCC(=O)C(=O)OC(C)(C)C)C=C1 PAGFOTUDGKPNMP-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- Novel N-carboxyalkylpeptidyl compounds of formula I are fou nd to be usef u l in h ibitors of matrix metal loe ndoprote in ase-med iated diseases i n cl udi ng osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion in certain cancers, periodontal disease, corneal ulceration, proteinuria, dystrophobic epidermolysis bullosa, and coronary thrombosis associated with atherosclerotic plaque rupture.
- the matrix metalloendoproteinases are a family of zinc-containing proteinases including but not limited to stromelysin, collagenase, and gelatinase, that are capable of degrading the major components of articular cartilage and basement membranes.
- the inhibitors claimed herein may also be useful in preventing the pathological sequelae following a traumatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation.
- OA osteoarthritis
- RA rheumatoid arthritis
- DMARD Disease modifying antirheumatic drugs
- NSAIDs Generic nonsteroidal antiinflammatory drugs
- type IV collagenase, matrix metaIloproteinase-2, MMP-2, 72kDa-gelatinase or type V collagenase, matrix metalloproteinase-9, MMP-9, 95kDa- gelatinase) are metalloendoproteinases secreted by fibroblasts and chondrocytes, and are capable of degrading the major connective tissue components of articular cartilage or basement membranes. Elevated levels of both enzymes have been detected in joints of arthritic humans and animals: K.A. Hasty, R.A. Reife, A.H. Kang, J.M.
- stromelysin may be the in vivo activator for collagenase, implying a cascade for degradative enzyme activity: A. Ho, H. Nagase, "Evidence that human rheumatoid synovial matrix metalloproteinase 3 is an endogenous activator of procollagenase", Arch Biochem Biophys., 267, 211 -16 (1988); G. Murphy, M.I. Crockett, P.E. Stephens, B.J. Smith, A.J.P.
- That stromelysin inhibition may be effective in preventing articular cartilage degradation has been demonstrated in vitro by measuring the effect of matrix metalloendoproteinase inhibitors on proteoglycan release from rabbit cartilage explants: C.B. Caputo, LA. Sygowski, S.P. Patton, D.J. Wolanin, A. Shaw, R.A. Roberts, G. DiPasquale, J. Orthopaedic Res., 6, 103-8 (1988).
- Gelatinase (MR ⁇ 72,000) has been isolated from rheumatoid fibroblasts: Y. Okada, T. Morodomi, J. J. Enghiid, K. Suzuki, A. Yasui, I. Nakanishi, G. Salvesen, H. Nagase, "Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts", Eur. J., Biochem., 194, 721-30 (1990). The synthesis of the proenzyme is not coordinately regulated with the other two metalloproteinases and its activation may also be different.
- gelatinase in the tissue destruction of articular cartilage appears different from the other two enzymes and, therefore, its inhibition may provide additional protection from degradation.
- a higher molecular weight gelatinase (MR ⁇ 95,000; aka. type-V collagenase, matrix metalloproteinase-9, MMP-9) is also secreted by fibroblasts and monocytes and may be involved in cartilage degradation.
- stromelysin and collagenase inhibitors have utility in preventing articular cartilage damage associated with septic arthritis.
- Bacterial infections of the joints can elicit an inflammatory response that may then be perpetuated beyond what is needed for removal of the infective agent resulting in permanent damage to structural components.
- Bacterial agents have been used in animal models to elicit an arthritic response with the appearance of proteolytic activities. See J.P. Case, J. Sano, R. Lafyatis, E.F. Remmers, G.K. Kumkumian, R.L. Wilder, "Transin/stromelysin expression in the synovium of rats with experimental erosive arhtritis", J.
- Secreted proteinases such as stromelysin, collagenase, and gelatinase play an important role in processes involved in the movement of cells during metastasic tumor invasion. Indeed, there is also evidence that the matrix metalloproteinases are overexpressed in certain metastatic tumor cell lines.
- the enzyme functions to penetrate underlying basement membranes and allow the tumor cell to escape from the site of primary tumor formation and enter circulation. After adhering to blood vessel walls, the tumor cells use these same metalloendoproteinases to pierce underlying basement membranes and penetrate other tissues, thereby leading to tumor metastasis. Inhibition of this process would prevent metastasis and improve the efficacy of current treatments with chemotherapeutics and/or radiation.
- Treatment of alkali-burned eyes or eyes exhibiting corneal ulceration as a resu lt of i nfectio n with i n h ibitors of these metalloendoproteinases in combination with sodium citrate or sodium ascorbate and/or antimicrobials may be effective in preventing developing corneal degradation.
- Stromelysin has been implicated in the degradation of structural components of the glomerular basement membrane (GBM) of the kidney, the major function of which is to restrict passage of plasma proteins into the urine; W.H. Baricos, G. Murphy, Y. Zhou, H.H. Nguyen, S.V. Shah, "Degradation of glomerular basement membrane by purified mammalian metalloproteinases", Biochem. J., 254, 609-612 (1988).
- Proteinuria a result of glomerular disease, is excess protein in the urine caused by increased permeability of the GBM to plasma proteins.
- the underlying causes of this increased GBM permeability are unknown, but proteinases including stromelysin may play an important role in glomerular diseases. Inhibition of this enzyme may alleviate the proteinura associated with kidney malfunction.
- stromelysin activity may prevent the rupturing of atherosclerotic plaques leading to coronary thrombosis.
- the tearing or rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis.
- Destabilization and degradation of the connective tissue matrix surrounding these plaques by proteolytic enzymes or cytokines released by infiltrating inflammatory cells has been proposed as a cause of plaque fissuring.
- Such tearing of these plaques can cause an acute thrombolytic event as blood rapidly flows out of the blood vessel.
- High levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery: A. M.
- stromelysin and collagenase should be useful as birth control agents.
- expression of metalloendoproteinases, including stromelysin and collagenase is observed in unfertilized eggs and zygotes and at further cleavage stages and increased at the blastocyst stage of fetal development and with endoderm differentiation: CA. Brenner, R.R. Adler, D.A. Rappolee, R.A. Pedersen, Z. Werb, "Genes for extracellular matrix-degrading metalloproteinases and their inhibitor, TIMP, are expressed during early mammalian development", Genes & Develop., 3, 848-59 (1989).
- a blastocyst may express metalloproteinases in order to penetrate the extracellular matrix of the uterine wall during implantation. Inhibition of stromelysin and collagenase during these early developmental processes should presumably prevent normal embryonic development and/or implantation in the uterus. Such intervention would constitute a novel method of birth control.
- collagenase is important in ovulation processes. In this example, a covering of collagen over the apical region of the follicle must be penetrated in order for the ovum to escape. Collagenase has been detected during this process and an inhibitor has been shown to be effective in preventing ovulation: J.F. Woessner, N.
- Collagenolytic and stromelysin activity have also been observed in dystrophobic epidermolysis bullosa: A. Kronberger, K.J. Valle, A.Z. Eisen, E.A. Bauer, J. Invest. Dermatol., 79 208-211 (1982); D. Sawamura, T. Sugawara, I. Hashimoto, L. Bruckmer-Tuderman, D. Fujimoto, Y. Okada, N. Utsumi, H. Shikata, Biochem. Biophys. Res. Commun., 174, 1003-8 (1991 ). Inhibition of metalloendoproteinases should limit the rapid destruction of connective components of the skin.
- stromelysin can degrade other in vivo substrates including the inhibitors ⁇ 1 -proteinase inhibitor and may therefore influence the activities of other proteinases such as elastase: P. G. Winyard, Z. Zhang, K. Chidwick, D. R. Blake, R. W. Carrell, G. Murphy, "Proteolytic inactivation of human ⁇ 1 -antitrypsin by human stromelysin", FEBS Letts., 279, 1 , 91-94 (1991 ). Inhibition of the matrix metalloendoproteinases may potentiate the antiproteinase activity of these endogenous inhibitors.
- the invention encompasses novel N-carboxy-alkylpeptidyl compounds of formula I which are useful inhibitors of matrix metalloendoproteinase-mediated diseases including degenerative diseases (such as defined above) and certain cancers.
- R 1 is substituted C 1-6 alkyl, wherein the substituent is selected from the group consisting of:
- substitutents are independently selected from C 1- 6 alkryl, C 1- 6 alkryloxy, halo, hydroxy, amino, C 1-6 alkrylamino, amino C 1-6 alkryl, carboxyl, carboxyl C 1- 6 alkryl, and C 1- 6 alkrylcarbonyl;
- R b wherein R a and R b are each independently hydrogen; C 6 -10 aryl an d mono and di-substituted C 6 -10 aryl as defined above (d); or substituted C 1- 6 alkryl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactam or benzolactam ring wherein the lactam portion thereof is a ring of up to 8 atoms, said lactam or benzolactam have a single hetero atom;
- R a and Rb are each independently hydrogen; C 6 -10 aryl and mono and di- substituted C 1- 6 alkryl as defined above (d); or substituted C 1- 6 alkryl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactim or benzolactim ring wherein the lactim portion thereof is a ring of up to 8 atoms, said lactim or benzolactim have a single hetero atom;
- R 2 is CHR c R d wherein
- R c is (a) H
- R d is C 6-10 aryl C 1-2 alkryl or C 6-10 aryl substituted
- C 6 -10 aryl as defined above in items (1) to (27) wherein the substitutents are independently selected from C 1- 6 alkryl.
- R 3 is (a) H
- substituted phenyl wherein the substitutent is carboxy, carboxy C 1- 3 alkryl , aminocarbonyl, C 1- 6 alkrylaminocarbonyl;
- AA is an amino acid of formula II
- R e and R f are individually selected from:
- the above amino acids of formula II are intended to include but are not limited to glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxylysine, arginine, homohistidine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, omithine, homoserine, and citrulline.
- One genus of this embodiment is the compounds wherein: substituted C 1 -6 alkyl, wherein the substituent is selected from the group consisting of:
- R c is (a) H
- a sub-class of this class is the compounds wherein:
- AA is an amino acid including glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxy-lysine, homohistidine, arginine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, ornithine, homoserine, or citrulline.
- amino acids AA can be defined as follows: A is R e O
- R e and Rf are individually selected from:
- R 5 and R 6 are each individually selected from the group consisting of
- R d is C 1-4 alkyl C 6-10 aryl C 1-2 alkyl
- R 3 is (a) H, or
- R 1 is C 6-10 aryl C 1-6 alkyl
- R b is H.
- This invention also concerns pharmaceutical composition and methods of treatment of stromelysin-mediated or implicated disorders or diseases (as described above) in a patient (whcih shall be defined to include man and/or mammalian animals raised in the dairy, meat, or fur industries or as pets) in need of such treatment comprising administration of the stromelysin inhibitors of formula I as the active constituents.
- this invention also concerns pharmaceutical compositions and methods of treatment of collagenase mediated or implicated disorders or diseases (as described above) in a patient in need of such treatment comprising administration of the collagenase inhibitors of formula (I) as the active constituents.
- Si m i larly, th is inve ntion also conce rns pharmaceutical compositions and methods of treatment of gelatinase-mediated or implicated disorders or diseases (as described above) in a patient in need of such treatment comprising administration of the gelatinase inhibitors of formula (I) as the active constituents.
- compositions, treatment, and method for co-administration of a compound of formula I with a PMN elastase inhibitor such as those described in EP 0 337 549 which published on October 18, 1989, which is hereby incorporated by reference.
- This reaction sequence advantageously employs the use of condensing agents such as dicyclohexylcarbodiimide (DDC) or water-soluble carbodiimide (N-ethyl-N'-(3-diethylaminopropyl)-carbodiimide; EDC).
- DDC dicyclohexylcarbodiimide
- EDC water-soluble carbodiimide
- This reaction is also assisted by the formation of active ester intermediates such as those derived from 1 - hydroxybenzotriazole, 4-nitrophenol, or 4-picolyl alcohol.
- the amino acid derivatives [AA]-X are prepared from appropriately protected N-protected amino acid derivatives condensed with X under similar conditions cited for the formation of D.
- a representative number of compounds of the instant invention of the formula (I) are shown below to exhibit in vitro inhibitory activities with respect to stromelysin, collagenase, and gelatinase.
- the compounds of formula (I) have been shown to inhibit the hydrolysis of substance P, (that is, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 ) by stromelysin employing the method described in detail in the literature: R. Harrison, J. Teahan, R. Stein, "A semicontinuous, high-performance liquid chromatography-based assay for stromelysin", Analytical Biochem, 180, 1 10-113 (1989).
- This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat, or fur industries or as pets) suffering from disorders or diseases which can be attributed to stromelysin as previously described, and more specifically, a method of treatment involving the administration of the matrix metalloendoproteinase inhibitors of formula (I) as the active constituents.
- the compounds of formula (I) can be used among other things in the treatment of osteoarthritis and rheumatoid arthritis, and in diseases and indications resulting from the over-expression of these matrix metalloendoproteinases such as found in certain metastatic tumor cell lines.
- the compounds of formula 1 For the treatment of rheumatoid arthritis, osteoarthritis, and in diseases and indications resulting from the over-expression of matrix metalloendoproteinases such as found in certain metastatic tumor cell lines or other diseases mediated by the matrix metalloendoproteinases, the compounds of formula
- (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
- the compounds of the invention are effective in the treatment of humans.
- compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
- the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formula (I) are employed.
- topical application shall include mouth washes and gargles.
- Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above- indicated conditions (about 2.5 mg to about 7 gms. per patient per day).
- inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 gms per patient per day).
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
- Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
- the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
- aqueous slurry (containing the desired HCI salt) was then extracted three times with ethyl acetate and the combined organic layers were washed three times with saturated aqueous sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 20 g of a yellow oil.
- amino acid ester 1 was prepared as a single diastereomer and converted to compound 5a using methodology described in Example 1.
- N,N- diisopropylethylamine (4.0 mL, 23.0 mmol) was added followed immediately by a solution of (L)-homophenylalanine t-butyl ester (4.97 g, 21.1 mmol) in methylene chloride (40 mL) dropwise over 15 minutes with stirring. The cooling bath was then removed, and the mixture was stirred for 24 hours at room temperature. The mixture was diluted with methylene chloride (150 mL) which was successively washed with water, saturated aqueous sodium bicarbonate solution, saturated salt solution, dried over anhydrous magnesium sulfate and rotoevaporated.
- N-benzyloxycarbo-ethyl dipeptide 10 was prepared and converted to compound 5bk using methodology described in Example 1 for the preparation of 5a.
- N-trifluoroacetyl- ⁇ - ( S ) - (2- (4 - n - propylphenyl)ethyl)glycine 7 (127 mg, 0.40 mmol) in methylene chloride (10 mL) was cooled to 0° C under a dry nitrogen atmosphere.
- N-methyl morpholine (48 ⁇ L, 0.44 mmol) was added followed by N-hydroxybenztriazole (81 mg, 0.6 mmol).
- Ammonia gas was bubbled into methanol (20 mL) at -20° C for 30 minutes then placed in a pressure tube with N- trifluoroacetyl- ⁇ - (S)-(2-(4-n-propylphenyl)ethyl)g lycine- (L)- leucine, N-phenylamide 8 (120 mg, 0.23 mmol), sealed, and stirred at room temperature for 5 days.
- the tube was cooled to -20 ⁇ C before opening and then the solvent was evaporated in vacuo.
- the product was purified by preparative thin layer chromatography on silica gel eluted with 2% methanol in chloroform (95 mg, 100% yield).
- dipeptide 14 was prepared and converted to compound 5bq using methodology described in Example 4 for the preparation of 5bk.
- THF cuprate solution Approximately half of the THF cuprate solution (-1.4 mmol) was diluted in dry THF (20 mL) and cooled to 0 ⁇ C. This solution was slowly added via a syringe pump over a period of 1 hour to a solution of N-carbobenzyloxy- ⁇ - ( S ) - ( 2 - iodoethyl)lglycine, methyl ester (277 mg, 0.70 mmol) in THF (5 mL). The solution was stirred at room temperature for 5 hours. The reaction was quenched with 10% ammonium chloride solution (5 mL) and extracted with methylene chloride (3 ⁇ 20 mL).
- N-Carbobenzyloxy- ⁇ -(S)- (3 , 4- dimethylphenethyl)glycine 12 (207 mg, 0.55 mmol), (L)-leucine, N-phenylamide (125 mg, 0.61 mmol), N-hydroxybenztriazole (87 mg, 0.66 mmol), and N-methyl morpholine (130 ⁇ L, 1.1 mmol) in THF (3 mL) was stirred at room temperature for 10 minutes. EDAC (158 mg, 0.83 mmol) was added and the solution stirred for 4 hours.
- N-phenylamide (148 mg) was added 10 mg of 10% palladium on carbon in a 10 ml round bottom flask fitted with a stirring bar and rubber septum. The flask was flushed with hydrogen via syringe attached to a balloon reservoir. Stirring was continued for 1 hr, during which the starting material was converted to product and the reaction mixture became homogeneous. Filtration through a 2 micron filter removed the palladium catalyst and the methanol solvent was removed under reduced pressure. The product was recovered (8g mg, 98% yield) and used in the subsequent step without purification.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5500416A JPH06508135A (ja) | 1991-05-28 | 1992-05-01 | 抗変性活性剤としての置換n−カルボキシアルキルペプチジル誘導体 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US70582691A | 1991-05-28 | 1991-05-28 | |
US705,826 | 1991-05-28 | ||
US87390592A | 1992-04-24 | 1992-04-24 | |
US873,905 | 1992-04-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992021360A1 true WO1992021360A1 (fr) | 1992-12-10 |
Family
ID=27107579
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1992/003809 WO1992021360A1 (fr) | 1991-05-28 | 1992-05-01 | Derives substitues n-carboxyalkylpeptidyle en tant qu'agents antidegeneratifs |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0586537A4 (fr) |
JP (1) | JPH06508135A (fr) |
CA (1) | CA2102890A1 (fr) |
WO (1) | WO1992021360A1 (fr) |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5326760A (en) * | 1992-06-29 | 1994-07-05 | Glaxo, Inc. | Aminobutanoic acid compounds having metalloprotease inhibiting properties |
WO1995004735A1 (fr) * | 1993-08-05 | 1995-02-16 | Syntex (U.S.A.) Inc. | Inhibiteurs de la metalloprotease matricielle |
US5403952A (en) * | 1993-10-08 | 1995-04-04 | Merck & Co., Inc. | Substituted cyclic derivatives as novel antidegenerative agents |
WO1995009620A1 (fr) * | 1993-10-06 | 1995-04-13 | Florida State University | Sulfoximine et sulfodiimine inhibitrices la metalloproteinase matrice |
US5455262A (en) * | 1993-10-06 | 1995-10-03 | Florida State University | Mercaptosulfide metalloproteinase inhibitors |
WO1995029689A1 (fr) * | 1994-04-28 | 1995-11-09 | Merck & Co., Inc. | Derives de n-carboxyalkyle utilises comme agents antidegeneratifs |
WO1996023791A1 (fr) * | 1995-02-03 | 1996-08-08 | Syntex (U.S.A.) Inc. | Indoles pontes utilises comme inhibiteurs de metalloproteases matricielles |
WO1996033733A1 (fr) * | 1995-04-25 | 1996-10-31 | Fuji Yakuhin Kogyo Kabushiki Kaisha | Nouveau remede pour affections cutanees |
US5747514A (en) * | 1994-01-20 | 1998-05-05 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
US5773428A (en) * | 1993-08-05 | 1998-06-30 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
US5919940A (en) * | 1995-01-20 | 1999-07-06 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
US5932595A (en) * | 1995-12-20 | 1999-08-03 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
US5985900A (en) * | 1997-04-01 | 1999-11-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
US6008243A (en) * | 1996-10-24 | 1999-12-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
US6037472A (en) * | 1993-11-04 | 2000-03-14 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
US6153757A (en) * | 1995-12-08 | 2000-11-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors and intermediates useful for their preparation |
US6169075B1 (en) | 1996-09-10 | 2001-01-02 | British Biotech Pharmaceuticals Limited | Cytostatic agents |
US6174915B1 (en) | 1997-03-25 | 2001-01-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
US6281352B1 (en) | 1995-11-14 | 2001-08-28 | Dupont Pharmaceuticals Company | Macrocyclic compounds as metalloprotease inhibitors |
US6462023B1 (en) | 1996-09-10 | 2002-10-08 | British Biotech Pharmaceuticals, Ltd. | Cytostatic agents |
US6500948B1 (en) | 1995-12-08 | 2002-12-31 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof |
WO2001082911A3 (fr) * | 2000-04-28 | 2003-03-13 | Michel Xilinas | Traitement d'etats pathologiques influences par l'action de metalloprotease de matrice (mmp) au moyen de clioquinol |
US6576664B1 (en) | 1997-08-18 | 2003-06-10 | Bristol-Myers Squibb Pharma Company | Inhibitors of aggrecanase and matrix metalloproteinases for the treatment of arthritis |
WO2004033439A1 (fr) * | 2002-10-09 | 2004-04-22 | Pfizer Products Inc. | Composes thiazole utiles pour le traitement des maladies neurodegeneratives |
WO2004099200A1 (fr) * | 2003-05-12 | 2004-11-18 | Pfizer Products Inc. | Composes isoxazoliques et isothiazoliques destines au traitement de troubles neurodegeneratifs |
US7022846B2 (en) | 2002-06-10 | 2006-04-04 | Agouron Pharmaceuticals, Inc. | Metabolites of prinomastat and their synthesis |
WO2006117660A3 (fr) * | 2005-05-04 | 2007-01-04 | Clio Pharmaceutical Corp | Methode de traitement du cancer et des maladies coronaire, inflammatoire et maculaire combinant la modulation de proteines dependantes du zinc et/ou du cuivre |
US7846963B2 (en) | 2003-05-17 | 2010-12-07 | Korea Research Institute Of Bioscience And Biotechnology | 2-oxo-heterocyclic compounds and the pharmaceutical compositions comprising the same |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4511504A (en) * | 1983-04-26 | 1985-04-16 | G.D. Searle & Co. | Carboxyalkyl peptide derivatives |
US4568666A (en) * | 1984-10-18 | 1986-02-04 | G. D. Searle & Co. | Carboxylalkyl peptide derivatives |
US4771037A (en) * | 1986-01-21 | 1988-09-13 | Ici Americas Inc. | N-carboxyalkyl compounds |
-
1992
- 1992-05-01 WO PCT/US1992/003809 patent/WO1992021360A1/fr not_active Application Discontinuation
- 1992-05-01 EP EP92912475A patent/EP0586537A4/en not_active Withdrawn
- 1992-05-01 JP JP5500416A patent/JPH06508135A/ja not_active Withdrawn
- 1992-05-01 CA CA002102890A patent/CA2102890A1/fr not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4511504A (en) * | 1983-04-26 | 1985-04-16 | G.D. Searle & Co. | Carboxyalkyl peptide derivatives |
US4568666A (en) * | 1984-10-18 | 1986-02-04 | G. D. Searle & Co. | Carboxylalkyl peptide derivatives |
US4771037A (en) * | 1986-01-21 | 1988-09-13 | Ici Americas Inc. | N-carboxyalkyl compounds |
Non-Patent Citations (1)
Title |
---|
See also references of EP0586537A4 * |
Cited By (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5326760A (en) * | 1992-06-29 | 1994-07-05 | Glaxo, Inc. | Aminobutanoic acid compounds having metalloprotease inhibiting properties |
WO1995004735A1 (fr) * | 1993-08-05 | 1995-02-16 | Syntex (U.S.A.) Inc. | Inhibiteurs de la metalloprotease matricielle |
US5773428A (en) * | 1993-08-05 | 1998-06-30 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
US5470834A (en) * | 1993-10-06 | 1995-11-28 | Florida State University | Sulfoximine and suldodiimine matrix metalloproteinase inhibitors |
US5455262A (en) * | 1993-10-06 | 1995-10-03 | Florida State University | Mercaptosulfide metalloproteinase inhibitors |
WO1995009620A1 (fr) * | 1993-10-06 | 1995-04-13 | Florida State University | Sulfoximine et sulfodiimine inhibitrices la metalloproteinase matrice |
US5403952A (en) * | 1993-10-08 | 1995-04-04 | Merck & Co., Inc. | Substituted cyclic derivatives as novel antidegenerative agents |
US6037472A (en) * | 1993-11-04 | 2000-03-14 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
US6579890B1 (en) | 1993-11-04 | 2003-06-17 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
US5747514A (en) * | 1994-01-20 | 1998-05-05 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
US5859253A (en) * | 1994-01-20 | 1999-01-12 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
WO1995029689A1 (fr) * | 1994-04-28 | 1995-11-09 | Merck & Co., Inc. | Derives de n-carboxyalkyle utilises comme agents antidegeneratifs |
US5919940A (en) * | 1995-01-20 | 1999-07-06 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
WO1996023791A1 (fr) * | 1995-02-03 | 1996-08-08 | Syntex (U.S.A.) Inc. | Indoles pontes utilises comme inhibiteurs de metalloproteases matricielles |
WO1996033733A1 (fr) * | 1995-04-25 | 1996-10-31 | Fuji Yakuhin Kogyo Kabushiki Kaisha | Nouveau remede pour affections cutanees |
US6281352B1 (en) | 1995-11-14 | 2001-08-28 | Dupont Pharmaceuticals Company | Macrocyclic compounds as metalloprotease inhibitors |
US6153757A (en) * | 1995-12-08 | 2000-11-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors and intermediates useful for their preparation |
US6500948B1 (en) | 1995-12-08 | 2002-12-31 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof |
US5932595A (en) * | 1995-12-20 | 1999-08-03 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
US6462023B1 (en) | 1996-09-10 | 2002-10-08 | British Biotech Pharmaceuticals, Ltd. | Cytostatic agents |
US6169075B1 (en) | 1996-09-10 | 2001-01-02 | British Biotech Pharmaceuticals Limited | Cytostatic agents |
US6495699B2 (en) | 1996-10-24 | 2002-12-17 | Agouron Pharmaceuticals Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
US6008243A (en) * | 1996-10-24 | 1999-12-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
US6306892B1 (en) | 1997-03-25 | 2001-10-23 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
US6174915B1 (en) | 1997-03-25 | 2001-01-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
US5985900A (en) * | 1997-04-01 | 1999-11-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
US6576664B1 (en) | 1997-08-18 | 2003-06-10 | Bristol-Myers Squibb Pharma Company | Inhibitors of aggrecanase and matrix metalloproteinases for the treatment of arthritis |
WO2001082911A3 (fr) * | 2000-04-28 | 2003-03-13 | Michel Xilinas | Traitement d'etats pathologiques influences par l'action de metalloprotease de matrice (mmp) au moyen de clioquinol |
US7022846B2 (en) | 2002-06-10 | 2006-04-04 | Agouron Pharmaceuticals, Inc. | Metabolites of prinomastat and their synthesis |
WO2004033439A1 (fr) * | 2002-10-09 | 2004-04-22 | Pfizer Products Inc. | Composes thiazole utiles pour le traitement des maladies neurodegeneratives |
WO2004099200A1 (fr) * | 2003-05-12 | 2004-11-18 | Pfizer Products Inc. | Composes isoxazoliques et isothiazoliques destines au traitement de troubles neurodegeneratifs |
US7241786B2 (en) | 2003-05-12 | 2007-07-10 | Pfizer Inc | Isoxazole and isothiazole compounds for the treatment of neurodegenerative disorders |
US7846963B2 (en) | 2003-05-17 | 2010-12-07 | Korea Research Institute Of Bioscience And Biotechnology | 2-oxo-heterocyclic compounds and the pharmaceutical compositions comprising the same |
WO2006117660A3 (fr) * | 2005-05-04 | 2007-01-04 | Clio Pharmaceutical Corp | Methode de traitement du cancer et des maladies coronaire, inflammatoire et maculaire combinant la modulation de proteines dependantes du zinc et/ou du cuivre |
Also Published As
Publication number | Publication date |
---|---|
EP0586537A1 (fr) | 1994-03-16 |
JPH06508135A (ja) | 1994-09-14 |
EP0586537A4 (en) | 1997-06-25 |
CA2102890A1 (fr) | 1992-11-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1992021360A1 (fr) | Derives substitues n-carboxyalkylpeptidyle en tant qu'agents antidegeneratifs | |
US5672583A (en) | Carboxy-peptidyl derivatives as antidegenerative active agents | |
US5387610A (en) | Peptide derivatives of collagenase inhibitor | |
US5679700A (en) | Substituted phosphinic acid-containing peptidyl derivatives as antidegenerative agents | |
AU679286B2 (en) | Peptidyl compounds and their therapeutic use as inhibitors of metalloproteinases | |
KR100352316B1 (ko) | 메탈로프로테아제억제제로서사용되는술포닐아미노치환히드록삼산유도체 | |
US5403952A (en) | Substituted cyclic derivatives as novel antidegenerative agents | |
JPH09500087A (ja) | カルパイン活性の増大に関連した健康障害の抑制及び処置におけるカルパイン阻害剤の使用法 | |
FR2609289A1 (fr) | Nouveaux composes a activite d'inhibiteurs de collagenase, procede pour les preparer et compositions pharmaceutiques contenant ces composes | |
KR20000035925A (ko) | 매트릭스 메탈로프로테아제 저해제인 포스핀산 아미드 | |
JPH05271274A (ja) | インターロイキン−1β変換酵素阻害剤としてのペプチド性誘導体 | |
KR20020008168A (ko) | Ace-2 억제 화합물 및 이의 사용 방법 | |
FR2778406A1 (fr) | Derives d'alpha-cetoamides, procede pour leur preparation, preparations pharmaceutiques les contenant, et leur utilisation en tant que medicaments anti-viraux | |
PL185312B1 (pl) | Tiopodstawione peptydy, zawierające je środki farmaceutyczne i ich zastosowanie | |
JP2002514180A (ja) | マトリックスメタロプロテイナーゼを阻害するための化合物およびその方法 | |
US5629343A (en) | N-(mercaptoacyl) peptidyl derivatives as antidegenerative agents | |
US5508266A (en) | Gem-disubstituted amino acid derivatives | |
US5506244A (en) | Cyclic amino acid derivatives | |
EP0655461A1 (fr) | Dérivés d'amino acide cycliques ayant une activité inhibante d'ACE et NEP | |
US6090785A (en) | Substituted N-carboxyalkylpeptidyl derivatives as antidegenerative agents | |
US5932551A (en) | Substituted N-carboxyalkylpeptidyl derivatives as antidegenerative active agents | |
JP3354941B2 (ja) | マトリックス・メタロプロテアーゼ阻害物質としての置換4―アリール酪酸誘導体 | |
EP1060161B1 (fr) | Inhibiteurs de metalloprotease matricielle | |
WO1995029689A1 (fr) | Derives de n-carboxyalkyle utilises comme agents antidegeneratifs | |
HK1015139B (en) | Peptidyl compounds and their therapeutic use as inhibitors of metalloproteinases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2102890 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1992912475 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1992912475 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1992912475 Country of ref document: EP |