L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor

被引：65

作者：

Sanderson, PEJ ^{[1
]}

Cutrona, KJ

Dorsey, BD

Dyer, DL

McDonough, CM

Naylor-Olsen, AM

Chen, IW

Chen, ZG

Cook, JJ

Gardell, SJ

Krueger, JA

Lewis, SD

Lin, JH

Lucas, BJ

Lyle, EA

Lynch, JJ

Stranieri, MT

Vastag, K

Shafer, JA

Vacca, JP

机构：

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

[2] Merck Res Labs, Dept Biol Chem, W Point, PA 19486 USA

[3] Merck Res Labs, Dept Drug Metab, W Point, PA 19486 USA

[4] Merck Res Labs, Dept Mol Design & Divers, W Point, PA 19486 USA

[5] Merck Res Labs, Dept Pharmacol, W Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 1998年 / 8卷 / 07期

关键词：

D O I：

10.1016/S0960-894X(98)00117-6

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, K-i = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography. Published by Elsevier Science Ltd. All rights reserved.

引用

页码：817 / 822

页数：6

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