Orally active thrombin inhibitors.: Part 2:: Optimization of the P2-moiety

被引：27

作者：

Lange, UEW ^{[1
]}

Baucke, D

Hornberger, W

Mack, H

Seitz, W

Höffken, HW

机构：

[1] Abbott GmbH & Co KG, D-67061 Ludwigshafen, Germany

[2] BASF AG, D-67056 Ludwigshafen, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 10期

关键词：

thrombin inhibitor; anticoagulant; factor IIa inhibitor; serine protease inhibitor; amidine;

D O I：

10.1016/j.bmcl.2006.01.046

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Synthesis and SAR of orally active thrombin inhibitors of the D-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24 h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration. (C) 2006 Elsevier Ltd. All rights reserved.

引用

页码：2648 / 2653

页数：6

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