4‐Benzothiazole‐7‐hydroxyindolinyl Diaryl Ureas Are Potent P2Y1 Antagonists with Favorable Pharmacokinetics: Low Clearance and Small Volume of Distribution. Issue 10 (2nd July 2014)

• Record Type: Journal Article
• Authors: Qiao, Jennifer X.; Wang, Tammy C.; Hiebert, Sheldon; Hu, Carol H.; Schumacher, William A.; Spronk, Steven A.; Clark, Charles G.; Han, Ying; Hua, Ji; Price, Laura A.; Shen, Hong; Chacko, Silvi A.; Everlof, Gerry; Bostwick, Jeffrey S.; Steinbacher, Thomas E.; Li, Yi‐Xin; Huang, Christine S.; Seiffert, Dietmar A.; Rehfuss, Robert; Wexler, Ruth R.; Lam, Patrick Y. S.
• Is Part Of: ChemMedChem. Volume 9:Issue 10(2014:Oct.)
• Page Start: 2327
• Page End: 2343
• Publication Date: 2014-07-02
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402141
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 P2Y₁ antagonists may have lower bleeding liabilities than P2Y₁₂ 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 <bold>4</bold> was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF₃ group in <bold>4</bold> was then transformed to various groups via a novel one‐step synthesis, yielding a series of potent P2Y₁ 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 <bold>40</bold> had high i.v. exposure and modest bioavailability, giving it the best overall profile.</p> </abstract>