Conformationally constrained ortho-anilino diaryl ureas: discovery of 1-(2-(1'-neopentylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist.

Jennifer X Qiao, Tammy C Wang, Réjean Ruel, Carl Thibeault, Alexandre L'Heureux, William A Schumacher, Steven A Spronk, Sheldon Hiebert, Gilles Bouthillier, John Lloyd, Zulan Pi, Dora M Schnur, Lynn M Abell, Ji Hua, Laura A Price, Eddie Liu, Qimin Wu, Thomas E Steinbacher, Jeffrey S Bostwick, Ming Chang, Joanna Zheng, Qi Gao, Baoqing Ma, Patricia A McDonnell, Christine S Huang, Robert Rehfuss, Ruth R Wexler, Patrick Y S Lam

Index: J. Med. Chem. 56(22) , 9275-95, (2013)

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Abstract

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.