Journal
CHEMMEDCHEM
Volume 9, Issue 10, Pages 2327-2343Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201402141
Keywords
anionically active trifluoromethyl groups; antiplatelet; clearance; P2Y(1) antagonist; structure-activity relationships; volume of distribution
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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.
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