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WO1996039425A2 - Composes ayant une activite antagoniste de la bradykinine et une activite agoniste mu-opioïde - Google Patents

Composes ayant une activite antagoniste de la bradykinine et une activite agoniste mu-opioïde Download PDF

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Publication number
WO1996039425A2
WO1996039425A2 PCT/US1996/008923 US9608923W WO9639425A2 WO 1996039425 A2 WO1996039425 A2 WO 1996039425A2 US 9608923 W US9608923 W US 9608923W WO 9639425 A2 WO9639425 A2 WO 9639425A2
Authority
WO
WIPO (PCT)
Prior art keywords
arg
heterodimer
ser
pro
hyp
Prior art date
Application number
PCT/US1996/008923
Other languages
English (en)
Other versions
WO1996039425A3 (fr
Inventor
John C. Cheronis
Albert Gyorkos
Lyle W. Spruce
Eric T. Whalley
Original Assignee
Cortech, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US08/465,672 external-priority patent/US5843900A/en
Application filed by Cortech, Inc. filed Critical Cortech, Inc.
Priority to AU60444/96A priority Critical patent/AU6044496A/en
Priority to EP96918098A priority patent/EP0832106A2/fr
Publication of WO1996039425A2 publication Critical patent/WO1996039425A2/fr
Publication of WO1996039425A3 publication Critical patent/WO1996039425A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/18—Kallidins; Bradykinins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to compounds with combined bradykinin receptor antagonist and mu- opioid receptor agonist activities and to methods of using the same.
  • C-Fiber afferents are known to mediate both the sensation of pain as well as the neurogenic
  • neuropeptides include: substance-P, neurokinin A,
  • neurokinin B calcitonin gene related peptide (CGRP), cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), and neuropeptide Y, among other neurotransmitters.
  • CGRP calcitonin gene related peptide
  • CCK cholecystokinin
  • VIP vasoactive intestinal polypeptide
  • neuropeptide Y neuropeptide Y
  • molecular weight compounds such as morphine, oxymorphone, fentanyl and their derivatives will inhibit the release of the neuropeptides from peripheral C-fibers by acting as mu-opioid receptor agonists locally (at terminal mu-opioid receptors in the periphery) and in the CNS. This inhibition is independent of both the constellation of peptides contained in the specific C-fiber as well as the stimulus causing their release.
  • bradykinin antagonist BKAn
  • mu-opioid receptor agonist heterodimers These processes are bradykinin antagonist (BKAn)/mu-opioid receptor agonist heterodimers.
  • BKAn mu-opioid receptor agonists are due to their ability to easily penetrate the CNS.
  • BKAn mu-opioid receptor agonists are due to their ability to easily penetrate the CNS.
  • heterodimers should not penetrate the CNS due to the highly cationic nature of the BKAn.
  • mu-opioid receptor agonist activity should be limited to the periphery and
  • the present invention provides heterodimeric compounds of the general formula
  • BKAn bradykinin antagonist peptide
  • Y is a mu-opioid receptor agonist
  • X is a linking moiety. More specifically, the present invention provides heterodimeric compounds
  • mu-opioid receptor agonist is selected from fentanyl, dihydromorphine and morphine or derivatives or analogs thereof.
  • present invention also provides heterodimers comprising improved linking moieties as well as improved bradykinin antagonists.
  • Figure 1 shows the effect of dihydromorphine (DHM) on paw licking time following formalin injection.
  • Figure 2 shows the effect of CP-0840 on paw licking time following 10 ⁇ l formalin injection.
  • Figure 3 shows the effect of dihydo ⁇ norphine on the response time of mice exposed to a hot surface.
  • Figure 4 shows the effect of CP-0840 on the response time of mice exposed to a hot surface.
  • Figure 5 compares the effect of saline, DHM, CP-0597 and CP-0840 on carrageenan (1%
  • Figure 6 shows the duration of action of CP-0840 in rats.
  • Figure 7 compares the effect of saline, DHM, CP-0597 and CP-0840 on mustard oil induced neurogenic inflammation in the rat hind paw.
  • Figure 8 shows the effect of CP-0840 on the hypotensive response to bradykinin.
  • Figure 9 shows the selectivity of CP-0840.
  • the mu-opioid agonist is selected from fentanyl, dihydromorphine and morphine or derivatives or
  • Y is
  • R, and R 2 are independently selected from
  • Y is
  • Rl and R2 are independently selected from
  • R is a linking group X of the formula CH 2 CH 2 (Phe)CH 2 C(O); R 4 is COCH 2 CH 3 .
  • Preferred BKAn components include
  • any of the above peptides may be substituted with L- Arg or L-Lys in the "0" position (i.e., D-Arg).
  • the peptides may also be substituted with D- or L-Lys in the 0 to 6 positions for coupling to Y.
  • Linkage may then be accomplished for example, via the ⁇ -amino group of the L-Arg residue, or the ⁇ -amino or e-amino group of the D-Lys or L- Lys residue.
  • aqueous phase was acidified with IN aqueous hydrochloric acid and extracted with methylene
  • dihydro-17-methylmorphinan was prepared as follows: a) 4,5 «-Epoxy-3-O-acetyl-6- «-hydroxy-7,8-didehydro-17-methylmorphinan:
  • reaction mixture was transferred to a separatory funnel and extracted with chloroform (3x).
  • didehydro-17-methylmorphinan was prepared as follows: a) 4,5- «-Epoxy-3-triphenylmethoxy-6- «-hydroxy-7,8-didehydro-17-methylmo ⁇ hinan:
  • reaction mixture was diluted with methylene chloride and the organic phase separated.
  • the aqueous phase was further extracted with methylene chloride.
  • the combined organic layers were dried over magnesium sulfate. Filtration, removal of solvent, and column chromatography
  • reaction mixture was diluted with ethylacetate and washed with brine, then water.
  • Mass Spectral Analysis calculated (M+2) 1695; found (M+2) 1695.
  • reaction mixture was diluted with methylene chloride and
  • Example 4 The crude material was dissolved up into H 2 O/CH 3 CN/AcOH (8:2: 1) and purified by
  • piperidinyl]propanamide was prepared as follows: a) 4-(4-carbomethoxymethylphenyl amine)- 1 -(2-phenethyl)piperidine: '
  • reaction mixture was filtered through a plug of celite and
  • piperidinyljpropanamide and CP-0597 was prepared by a similar coupling method as described in
  • Example IV The crude heterodimer was dissolved into 10% AcOH/H 2 O and purified on RP-
  • reaction mixture was poured into 80g of ice containing 93 ml of concentrated ammonium
  • Example IV The crude heterodimer was purifed on RP-HPLC. Pure fraction were combined,
  • piperidinyljpropanamide was prepared as follows: a) N-phenyl-3-(2-carbomethoxyethyl)-N-[ 1 -(2-phenethyl)-4-piperdinyl]propanamide
  • the compounds were assayed for B2 receptor antagonist activity on guinea pig ileum,
  • a cDNA library from human brain was obtained from Stratagene. The
  • mu receptor sequence was selectively amplified from the cDNA library using nested PCR. The first
  • chloride-purified pRc/CMV (Invitrogen) was also digested with Hind HI and Xba I using standard methodology. The products of the two digests were resolved on a 0.7% low melt agarose gel.
  • Sections of gel containing the human mu receptor DNA (approximately 1.2 kb) and the pRc/CMV DNA (approximately 5.5 kb) were excised from the gel.
  • the gel slices containing these DNAs were heated at 65 °C and aliquots combined in a reaction containing T4 DNA ligase. The reaction was incubated overnight at 15°C. An aliquot of this reaction was used to transform frozen competent E.
  • nucleotide missinco ⁇ orations were detected and those that altered the amino acid sequence of the
  • Cesium chloride-purified human mu receptor-pRc/CMV plasmid was transfected into CHO-K1 (ATCC) cells using the Lipofectamine reagent (GibcoBRL). Transfectants were
  • hmu5 was chosen based upon binding levels, binding kinetics and inhibition patterns as the clone to
  • Binding assays were performed by incubating human clone membrane solution (50ug/well in 125 ul final concentration) with 3 H-DAMGO (final concentration 5nM) with or without test compounds in assay buffer , at room temperature, for 60 minutes, at a final volume of 315 ul. All test compound
  • RNA was isolated from human lung fibroblasts (CCD- 16 LU obtained from the ATCC) using
  • the first round PCR used the two primers CTCCGAGGAGGGGTGGG
  • PCR were done using the following conditions: 94°C, 1 minute for denaturation, 50°C, 1 minute for annealing followed by 72°C, 3 minutes for extension. Excess primers were removed with a Centricon
  • pRc CMV (Invitrogen) was also digested with Hind III and Xba I using standard methodology. The
  • CHO-Kl ATCQ cells using the Lipofectamine reagent (Gibco/BRL). Transfectants were selected
  • Buffer A consisting of 25mM TES(pH 6.8)with 2uM 1,10-Phenanthroline, and centrifuged at 27,000xg for 15 min. this was then repeated.
  • Buffer B Buffer A with 2uM Captopril,140ug/Ml Bacitracin, 0.1%BSA
  • Binding assays were performed by incubating human clone membrane solution (Approx.
  • Example XIX Mouse Formalin Test This test is a classical test for opiate and non-steroidal analgesic compounds. Mice are pretreated s.c. with vehicle or compound 30 minutes before injecting the formalin. lO ⁇ l of 5%
  • Figures 1 and 2 show the effect of dihydromo ⁇ hine and the heterodimer, CP-0840, both of
  • mice were placed on a surface maintained at 55°C and the
  • reaction time was recorded at time intervals up to 240 minutes.
  • the volume of the paw was measured before and after injection
  • test compounds were injected s.c. 30 min before injecting the carrageenan.
  • Carrageenan (1%) was
  • Figure 5 compares the effect of pretreatment of the rats with saline, dihydromorhine, CP-0597
  • CP-0840 (as does CP-0597) at this dose had a duration of action of greater than 6h in the rat against
  • CP-0840 is showing a clear co-operativity phenomenon possibly reflecting an opiate sensitive component during the second
  • Figure 7 compares the effect of dihydromo ⁇ hine, CP-0597 and CP-0840 in this model. At the doses used CP-0840 produced a significant inhibition of the edema response compared to saline controls.
  • bradykinin 80pM. These were repeated in the presence of increasing dose infusions
  • CP-0840 The dose of CP-0840 reducing the hypotensive response to bradykinin by 50% (ED50)
  • bradykinin 80pM
  • CP-0840 can be said to be a selective

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention se rapporte à des hétérodimères pharmaceutiquement efficaces comprenant un composant antagoniste de la bradykinine lié de manière covalente à un composant agoniste mu-opioïde.
PCT/US1996/008923 1995-06-05 1996-06-04 Composes ayant une activite antagoniste de la bradykinine et une activite agoniste mu-opioïde WO1996039425A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU60444/96A AU6044496A (en) 1995-06-05 1996-06-04 Compounds having bradykinin antagonistic activity and mu-opi oid agonistic activity
EP96918098A EP0832106A2 (fr) 1995-06-05 1996-06-04 Composes ayant une activite antagoniste de la bradykinine et une activite agoniste mu-opio de

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/465,672 1995-06-05
US08/465,672 US5843900A (en) 1991-04-01 1995-06-05 Bradykinin antagonists
US64716096A 1996-05-21 1996-05-21
US08/647,160 1996-05-21

Publications (2)

Publication Number Publication Date
WO1996039425A2 true WO1996039425A2 (fr) 1996-12-12
WO1996039425A3 WO1996039425A3 (fr) 1997-01-30

Family

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Family Applications (1)

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PCT/US1996/008923 WO1996039425A2 (fr) 1995-06-05 1996-06-04 Composes ayant une activite antagoniste de la bradykinine et une activite agoniste mu-opioïde

Country Status (4)

Country Link
EP (1) EP0832106A2 (fr)
AU (1) AU6044496A (fr)
TW (1) TW407159B (fr)
WO (1) WO1996039425A2 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1312923A3 (fr) * 2001-11-16 2003-08-13 Randox Laboratories Ltd. Méthode et trousse pour détecter, ou quantifier, des métabolites de fentanyl et des métabolites de fentanyl analogues
DE10081928B4 (de) * 1999-06-18 2006-06-08 Microgenics Corporation, Fremont 6-O-Acetylmorphin (6MAM)-Analoge Verbindungen, welche zur Verwendung in Immuntests geeignet sind, hiergegen gewonnene Antikörper, deren Herstellung sowie Reagentien und Reagenssysteme, die diese umfassen
US7109310B2 (en) 2001-11-16 2006-09-19 Randox Laboratories, Ltd. Method and kit for detecting, or determining the quantity of, metabolites of fentanyl and metabolites of fentanyl analogs
EP1810973A1 (fr) * 2005-12-16 2007-07-25 Roche Diagnostics GmbH Dérivés de 6-monoacetylmorphine utiles dans des dosages immunologiques
JP2008519837A (ja) * 2004-11-10 2008-06-12 ベーリンガー インゲルハイム ケミカルズ インコーポレイテッド フェンタニル中間体の生成方法
JP2013500256A (ja) * 2009-07-21 2013-01-07 ネクター セラピューティックス オリゴマー−オピオイドアゴニスト抱合体
US8569343B2 (en) 2007-03-12 2013-10-29 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE63490B1 (en) * 1988-11-24 1995-05-03 Hoechst Ag Peptides having bradykinin antagonist action
CZ203693A3 (en) * 1991-04-01 1994-07-13 Cortech Bradykinin antagonists
CA2106762C (fr) * 1991-04-19 2000-10-10 Donald J. Kyle Peptides antagonistes de la bradykinine
IL107400A0 (en) * 1992-11-10 1994-01-25 Cortech Inc Bradykinin antagonists
WO1995024422A1 (fr) * 1994-03-09 1995-09-14 Cortech, Inc. Peptides antagonistes de la bradykinine contenant des glycines substituees en n
US5648336A (en) * 1994-11-18 1997-07-15 University Of Colorado Bradykinin antagonist peptides containing indane-substituted amino acids

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10081928B4 (de) * 1999-06-18 2006-06-08 Microgenics Corporation, Fremont 6-O-Acetylmorphin (6MAM)-Analoge Verbindungen, welche zur Verwendung in Immuntests geeignet sind, hiergegen gewonnene Antikörper, deren Herstellung sowie Reagentien und Reagenssysteme, die diese umfassen
EP1312923A3 (fr) * 2001-11-16 2003-08-13 Randox Laboratories Ltd. Méthode et trousse pour détecter, ou quantifier, des métabolites de fentanyl et des métabolites de fentanyl analogues
US7109310B2 (en) 2001-11-16 2006-09-19 Randox Laboratories, Ltd. Method and kit for detecting, or determining the quantity of, metabolites of fentanyl and metabolites of fentanyl analogs
CN100402084C (zh) * 2001-11-16 2008-07-16 兰多克斯实验室有限公司 检测或定量芬太尼或其类似物的代谢物的方法和试剂盒
JP2008519837A (ja) * 2004-11-10 2008-06-12 ベーリンガー インゲルハイム ケミカルズ インコーポレイテッド フェンタニル中間体の生成方法
EP1810973A1 (fr) * 2005-12-16 2007-07-25 Roche Diagnostics GmbH Dérivés de 6-monoacetylmorphine utiles dans des dosages immunologiques
US8946285B2 (en) 2007-03-12 2015-02-03 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8569343B2 (en) 2007-03-12 2013-10-29 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8952032B2 (en) 2007-03-12 2015-02-10 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9233168B2 (en) 2007-03-12 2016-01-12 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9233167B2 (en) 2007-03-12 2016-01-12 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9458166B2 (en) 2007-03-12 2016-10-04 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9512135B2 (en) 2007-03-12 2016-12-06 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9827239B2 (en) 2007-03-12 2017-11-28 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10143690B2 (en) 2007-03-12 2018-12-04 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10307416B2 (en) 2007-03-12 2019-06-04 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates
JP2013500256A (ja) * 2009-07-21 2013-01-07 ネクター セラピューティックス オリゴマー−オピオイドアゴニスト抱合体

Also Published As

Publication number Publication date
TW407159B (en) 2000-10-01
EP0832106A2 (fr) 1998-04-01
AU6044496A (en) 1996-12-24
WO1996039425A3 (fr) 1997-01-30

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