4‐Benzothiazole‐7‐hydroxyindolinyl Diaryl Ureas Are Potent P2Y1 Antagonists with Favorable Pharmacokinetics: Low Clearance and Small Volume of Distribution

• DOI: 10.1002/cmdc.201402141
• Publication Date: 2014-07-02T21:34:38Z
• Authors: Jennifer X. Qiao; Tammy C. Wang; Sheldon Hiebert; Carol H. Hu; William A. Schuma...; Steven A. Spronk; Charles G. Clark; Ying Han; Ji Hua; Laura A. Price; Hong Shen; Silvi A. Chacko; Gerry Everlof; Jeffrey S. Bostwick; Thomas E. Steinba...; Yi‐Xin Li; Christine S. Huang; Dietmar A. Seiffert; Robert Rehfuss; Ruth R. Wexler; Patrick Y. S. Lam
• Keywords: Benzothiazole; Bleeding time

Abstract 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 P2Y 1 antagonists may have lower liabilities 12 while providing similar efficacy. This article describes our continuous SAR a series 7‐hydroxyindolinyl diaryl ureas. When dosed orally, 4‐trifluoromethyl‐7‐hydroxy‐3,3‐dimethylindolinyl analogue 4 was model arterial thrombosis rats limited bleeding. The chemically labile CF 3 group then transformed to various groups via novel one‐step synthesis, yielding potent antagonists. Among them, 4‐benzothiazole‐substituted indolines had desirable PK properties rats, specifically, low clearance and small volume distribution. In addition, compound 40 high i.v. exposure modest bioavailability, giving it best overall profile.