CA2201348A1 - Inhibiteurs de la transferase de proteines farnesylees exempts de thiol - Google Patents
Inhibiteurs de la transferase de proteines farnesylees exempts de thiolInfo
- Publication number
- CA2201348A1 CA2201348A1 CA 2201348 CA2201348A CA2201348A1 CA 2201348 A1 CA2201348 A1 CA 2201348A1 CA 2201348 CA2201348 CA 2201348 CA 2201348 A CA2201348 A CA 2201348A CA 2201348 A1 CA2201348 A1 CA 2201348A1
- Authority
- CA
- Canada
- Prior art keywords
- substituted
- alkyl
- unsubstituted
- aryl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 102000004357 Transferases Human genes 0.000 title claims description 32
- 108090000992 Transferases Proteins 0.000 title claims description 32
- 239000003112 inhibitor Substances 0.000 title abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 82
- 239000000203 mixture Substances 0.000 claims abstract description 80
- 230000006126 farnesylation Effects 0.000 claims abstract description 12
- 102000007317 Farnesyltranstransferase Human genes 0.000 claims abstract description 8
- 108010007508 Farnesyltranstransferase Proteins 0.000 claims abstract description 8
- 238000001727 in vivo Methods 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 315
- 125000003118 aryl group Chemical group 0.000 claims description 281
- 239000001257 hydrogen Substances 0.000 claims description 265
- 229910052739 hydrogen Inorganic materials 0.000 claims description 265
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 188
- 150000001875 compounds Chemical class 0.000 claims description 185
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 161
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 150
- 102200160920 rs35304565 Human genes 0.000 claims description 123
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 113
- 150000002431 hydrogen Chemical class 0.000 claims description 111
- 229940024606 amino acid Drugs 0.000 claims description 96
- 235000001014 amino acid Nutrition 0.000 claims description 96
- 150000001413 amino acids Chemical class 0.000 claims description 94
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 82
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 72
- 125000003342 alkenyl group Chemical group 0.000 claims description 65
- -1 heterosyclic Chemical group 0.000 claims description 60
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 58
- 102220389089 c.33G>T Human genes 0.000 claims description 53
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 45
- 102000016914 ras Proteins Human genes 0.000 claims description 42
- 108010014186 ras Proteins Proteins 0.000 claims description 42
- 125000000304 alkynyl group Chemical group 0.000 claims description 39
- 150000004702 methyl esters Chemical class 0.000 claims description 38
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 34
- UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 claims description 34
- 125000003107 substituted aryl group Chemical group 0.000 claims description 34
- 125000002883 imidazolyl group Chemical group 0.000 claims description 33
- 125000001041 indolyl group Chemical group 0.000 claims description 33
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 33
- 125000005494 pyridonyl group Chemical group 0.000 claims description 33
- 125000004076 pyridyl group Chemical group 0.000 claims description 33
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 33
- 125000000335 thiazolyl group Chemical group 0.000 claims description 33
- QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical compound C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 claims description 32
- QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 claims description 32
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 32
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 claims description 31
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 31
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000001544 thienyl group Chemical group 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 238000003556 assay Methods 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 15
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- MLBHNPAXTLCWTO-SDZVROEXSA-N (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 MLBHNPAXTLCWTO-SDZVROEXSA-N 0.000 claims description 11
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 9
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 9
- 235000004279 alanine Nutrition 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 230000005764 inhibitory process Effects 0.000 claims description 9
- 108090000623 proteins and genes Proteins 0.000 claims description 9
- OCUSNPIJIZCRSZ-ZTZWCFDHSA-N (2s)-2-amino-3-methylbutanoic acid;(2s)-2-amino-4-methylpentanoic acid;(2s,3s)-2-amino-3-methylpentanoic acid Chemical compound CC(C)[C@H](N)C(O)=O.CC[C@H](C)[C@H](N)C(O)=O.CC(C)C[C@H](N)C(O)=O OCUSNPIJIZCRSZ-ZTZWCFDHSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 229930182817 methionine Natural products 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- 235000018102 proteins Nutrition 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- ABXJKBIILDYYAG-ULOURMHMSA-N (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]-methylamino]-4-methylsulfanylbutanoic acid Chemical compound N([C@H](CN(CC(=O)N(C)[C@@H](CCSC)C(O)=O)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 ABXJKBIILDYYAG-ULOURMHMSA-N 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims description 4
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 claims description 4
- CSYHHWUWTASEFH-TVLMAONJSA-N propan-2-yl (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC(C)C)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 CSYHHWUWTASEFH-TVLMAONJSA-N 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- FOWLEPNFWOVZEA-WCUSUSPOSA-N (2s)-1-[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H]([C@@H](C)CC)NC(=O)CC=1N(C=NC=1)CC=1C=CC(=CC=1)C#N)N(CC=1C2=CC=CC=C2C=CC=1)CC(=O)N1CCC[C@H]1C(O)=O FOWLEPNFWOVZEA-WCUSUSPOSA-N 0.000 claims description 3
- BNHIGBMRWOTWFO-DZMJNENTSA-N (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-hydroxybutanoic acid Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCO)C(O)=O)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 BNHIGBMRWOTWFO-DZMJNENTSA-N 0.000 claims description 3
- FWWJGHORTZMPHN-SDZVROEXSA-N (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-methoxyphenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(OC)C=C1 FWWJGHORTZMPHN-SDZVROEXSA-N 0.000 claims description 3
- PVELUQSNQKSZDX-JTMVAAEOSA-N (2s)-2-[[2-[[(2s,3s)-3-methyl-2-[[(2s)-1-methyl-5-oxopyrrolidine-2-carbonyl]amino]pentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)[C@@H]1CCC(=O)N1C PVELUQSNQKSZDX-JTMVAAEOSA-N 0.000 claims description 3
- SJZGJLYNRZRTHV-UTEVTPAPSA-N (2s)-2-[[2-[[(2s,3s)-3-methyl-2-[[2-[3-(naphthalen-2-ylmethyl)imidazol-4-yl]acetyl]amino]pentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C1=CC=CC2=CC(CN3C=NC=C3CC(=O)N[C@H](CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=3C4=CC=CC=C4C=CC=3)[C@@H](C)CC)=CC=C21 SJZGJLYNRZRTHV-UTEVTPAPSA-N 0.000 claims description 3
- WWGONUOHFVVGEW-DZMJNENTSA-N (2s)-2-[[2-[[(2s,3s)-3-methyl-2-[[2-[3-[(4-nitrophenyl)methyl]imidazol-4-yl]acetyl]amino]pentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C([N+]([O-])=O)C=C1 WWGONUOHFVVGEW-DZMJNENTSA-N 0.000 claims description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 claims description 3
- 239000007995 HEPES buffer Substances 0.000 claims description 3
- WDBHLCLAOCYQSZ-ULOURMHMSA-N methyl (2s)-1-[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]pyrrolidine-2-carboxylate Chemical compound C([C@H]([C@@H](C)CC)NC(=O)CC=1N(C=NC=1)CC=1C=CC(=CC=1)C#N)N(CC=1C2=CC=CC=C2C=CC=1)CC(=O)N1CCC[C@H]1C(=O)OC WDBHLCLAOCYQSZ-ULOURMHMSA-N 0.000 claims description 3
- CBSHMRMVRKNMPY-WWTZYHKLSA-N methyl (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]-methylamino]-4-methylsulfanylbutanoate Chemical compound N([C@H](CN(CC(=O)N(C)[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 CBSHMRMVRKNMPY-WWTZYHKLSA-N 0.000 claims description 3
- HQFUINJGHRJKJL-DPGDXNODSA-N methyl (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 HQFUINJGHRJKJL-DPGDXNODSA-N 0.000 claims description 3
- FOWLEPNFWOVZEA-HBOJKDLWSA-N (2r)-1-[2-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H]([C@@H](C)CC)NC(=O)CC=1N(C=NC=1)CC=1C=CC(=CC=1)C#N)N(CC=1C2=CC=CC=C2C=CC=1)CC(=O)N1CCC[C@@H]1C(O)=O FOWLEPNFWOVZEA-HBOJKDLWSA-N 0.000 claims description 2
- MCKFIPGYQRGEOZ-SDZVROEXSA-N (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-methoxycarbonylphenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(O)=O)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C(=O)OC)C=C1 MCKFIPGYQRGEOZ-SDZVROEXSA-N 0.000 claims description 2
- NWEWKINOFDIBNL-FRJUPVQCSA-N (2s)-2-[[2-[benzyl-[(2s,3s)-3-methyl-2-[[2-[3-(naphthalen-2-ylmethyl)imidazol-4-yl]acetyl]amino]pentyl]amino]acetyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H]([C@@H](C)CC)NC(=O)CC=1N(C=NC=1)CC=1C=C2C=CC=CC2=CC=1)N(CC(=O)N[C@@H](CCSC)C(O)=O)CC1=CC=CC=C1 NWEWKINOFDIBNL-FRJUPVQCSA-N 0.000 claims description 2
- RPPZEKHGVVNKCF-GOJOWNLRSA-N (2s)-2-amino-4-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]-3-oxo-2-(2-sulfamoylethyl)butanoic acid Chemical compound N([C@H](CN(CC(=O)[C@@](N)(CCS(N)(=O)=O)C(O)=O)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 RPPZEKHGVVNKCF-GOJOWNLRSA-N 0.000 claims description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims description 2
- 239000012091 fetal bovine serum Substances 0.000 claims description 2
- 239000012742 immunoprecipitation (IP) buffer Substances 0.000 claims description 2
- PIAPBQYSIJZAPM-DPGDXNODSA-N methyl (2s)-2-[[2-[[(2s,3s)-2-[[2-[3-[(4-methoxyphenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(OC)C=C1 PIAPBQYSIJZAPM-DPGDXNODSA-N 0.000 claims description 2
- BTTAYOKAUFIVBM-SDZVROEXSA-N methyl (2s)-2-[[2-[[(2s,3s)-3-methyl-2-[[2-[3-[(4-nitrophenyl)methyl]imidazol-4-yl]acetyl]amino]pentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C([N+]([O-])=O)C=C1 BTTAYOKAUFIVBM-SDZVROEXSA-N 0.000 claims description 2
- ZKJHDKCBYLFQCD-MJVNWHNJSA-N methyl (2s)-2-[[2-[[(2s,3s)-3-methyl-2-[[2-[3-[naphthalen-2-yl(phenyl)methyl]imidazol-4-yl]acetyl]amino]pentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1C(C=1C=C2C=CC=CC2=CC=1)C1=CC=CC=C1 ZKJHDKCBYLFQCD-MJVNWHNJSA-N 0.000 claims description 2
- WHPZSXHSBYSSPK-YSXQJKROSA-N methyl (2s)-2-amino-4-[[(2s,3s)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]-3-oxo-2-(2-sulfamoylethyl)butanoate Chemical compound N([C@H](CN(CC(=O)[C@@](N)(CCS(N)(=O)=O)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 WHPZSXHSBYSSPK-YSXQJKROSA-N 0.000 claims description 2
- YDNJSKFZLXDYLX-DPGDXNODSA-N methyl 4-[[5-[2-[[(2s,3s)-1-[[2-[[(2s)-1-methoxy-4-methylsulfanyl-1-oxobutan-2-yl]amino]-2-oxoethyl]-(naphthalen-1-ylmethyl)amino]-3-methylpentan-2-yl]amino]-2-oxoethyl]imidazol-1-yl]methyl]benzoate Chemical compound N([C@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)CC=1C2=CC=CC=C2C=CC=1)[C@@H](C)CC)C(=O)CC1=CN=CN1CC1=CC=C(C(=O)OC)C=C1 YDNJSKFZLXDYLX-DPGDXNODSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 10
- 241000124008 Mammalia Species 0.000 claims 10
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
- 229920000936 Agarose Polymers 0.000 claims 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims 2
- 239000000499 gel Substances 0.000 claims 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims 2
- 239000002609 medium Substances 0.000 claims 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims 1
- 230000010307 cell transformation Effects 0.000 claims 1
- 229940009976 deoxycholate Drugs 0.000 claims 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims 1
- 230000009036 growth inhibition Effects 0.000 claims 1
- 239000012133 immunoprecipitate Substances 0.000 claims 1
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- 208000024891 symptom Diseases 0.000 description 1
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
- YJAAJMSZVZJPOQ-DTWKUNHWSA-N tert-butyl n-[(2s,3s)-3-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C YJAAJMSZVZJPOQ-DTWKUNHWSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000004589 thienofuryl group Chemical group O1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000004587 thienothienyl group Chemical group S1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Substances CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention porte sur des analogues du motif CAAX de la protéine Ras modifiés in vivo par farnésylation. Lesdits analogues, qui inhibent la farnésylation de la Ras, diffèrent par ailleurs de ceux précédemment décrits comme inhibiteurs de la Ras farnésyle transférase en ce qu'ils ne présentent pas de fraction thiol. Cette absence de thiol offre des avantages uniques en matière d'amélioration du comportement pharmacocinétique chez les animaux, de prévention des réactions chimiques liées aux thiols telles que la rapidité de l'auto-oxydation, la formation de bisulfures avec les thiols endogènes et une toxicité systémique réduite. L'invention porte également sur des compositions chimiothérapeutiques contenant les susdits inhibiteurs et sur leur procédé d'obtention.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US31497494A | 1994-09-29 | 1994-09-29 | |
| US314,974 | 1994-09-29 | ||
| US526,244 | 1995-09-21 | ||
| US08/526,244 US5652257A (en) | 1994-09-29 | 1995-09-21 | Heterocycle-containing inhibitors of farnesyl-protein transferase |
| PCT/US1995/012224 WO1996010034A2 (fr) | 1994-09-29 | 1995-09-26 | Inhibiteurs de la transferase de proteines farnesylees exempts de thiol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2201348A1 true CA2201348A1 (fr) | 1996-04-04 |
Family
ID=29407617
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2201348 Abandoned CA2201348A1 (fr) | 1994-09-29 | 1995-09-26 | Inhibiteurs de la transferase de proteines farnesylees exempts de thiol |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2201348A1 (fr) |
-
1995
- 1995-09-26 CA CA 2201348 patent/CA2201348A1/fr not_active Abandoned
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |