Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1)

被引：39

作者：

Nantermet, PG ^{[1
]}

Barrow, JC

Lundell, GF

Pellicore, JM

Rittle, KE

Young, M

Freidinger, RM

Connolly, TM

Condra, C

Karczewski, J

Bednar, RA

Gaul, SL

Gould, RJ

Prendergast, K

Selnick, HG

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Pharmacol, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Mol Design & Divers, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 03期

关键词：

D O I：

10.1016/S0960-894X(01)00745-4

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC50S of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min. (C) 2002 Published by Elsevier Science Ltd.

引用

页码：319 / 323

页数：5

共 32 条

[1] Structure-activity relationships of pyrroloquinazolines as thrombin receptor antagonists [J].

Ahn, HS ;

Arik, L ;

Boykow, G ;

Burnett, DA ;

Caplen, MA ;

Czarniecki, M ;

Domalski, MS ;

Foster, C ;

Manna, M ;

Stamford, AW ;

Wu, YS .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (14) :2073-2078

[2] A comparative SAR study of thrombin receptor derived non peptide mimetics: Importance of phenyl/guanidino proximity for activity [J].

Alexopoulos, K ;

Matsoukas, J ;

Tselios, T ;

Roumelioti, P ;

Mavromoustakos, T ;

Holada, K .

AMINO ACIDS, 1998, 15 (03) :211-220

[3] Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor [J].

Andrade-Gordon, P ;

Mayanoff, BE ;

Derian, CK ;

Zhang, HC ;

Addo, MF ;

Darrow, AL ;

Eckardt, AJ ;

Hoekstra, WJ ;

McComsey, DF ;

Oksenberg, D ;

Reynolds, EE ;

Santulli, RJ ;

Scarborough, RM ;

Smith, CE ;

White, KB .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (22) :12257-12262

[4] Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists [J].

Barrow, JC ;

Nantermet, PG ;

Selnick, HG ;

Glass, KL ;

Ngo, PL ;

Young, MB ;

Pellicore, JM ;

Breslin, MJ ;

Hutchinson, JH ;

Freidinger, RM ;

Condra, C ;

Karczewski, J ;

Bednar, RA ;

Gaul, SL ;

Stern, A ;

Gould, R ;

Connolly, TM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (20) :2691-2696

[5] Development of potent thrombin receptor antagonist peptides [J].

Bernatowicz, MS ;

Klimas, CE ;

Hartl, KS ;

Peluso, M ;

Allegretto, NJ ;

Seiler, SM .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (25) :4879-4887

[6]

Brass LF, 1997, THROMB HAEMOSTASIS, V78, P234

[7] Protease-activated receptors: sentries for inflammation? [J].

Cocks, TM ;

Moffatt, JD .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2000, 21 (03) :103-108

[8] AN ANTIBODY AGAINST THE EXOSITE OF THE CLONED THROMBIN RECEPTOR INHIBITS EXPERIMENTAL ARTERIAL THROMBOSIS IN THE AFRICAN-GREEN MONKEY [J].

COOK, JJ ;

SITKO, GR ;

BEDNAR, B ;

CONDRA, C ;

MELLOTT, MJ ;

FENG, DM ;

NUTT, RF ;

SHAFER, JA ;

GOULD, RJ ;

CONNOLLY, TM .

CIRCULATION, 1995, 91 (12) :2961-2971

[9] Thrombin signalling and protease-activated receptors [J].

Coughlin, SR .

NATURE, 2000, 407 (6801) :258-264

[10] How the protease thrombin talks to cells [J].

Coughlin, SR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (20) :11023-11027

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