期刊
CHEMMEDCHEM
卷 9, 期 10, 页码 2327-2343出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201402141
关键词
anionically active trifluoromethyl groups; antiplatelet; clearance; P2Y(1) antagonist; structure-activity relationships; volume of distribution
Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y(1) antagonists may have lower bleeding liabilities than P2Y(12) antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombo-sis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y(1) antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据