Journal of Medicinal Chemistry p. 9275 - 9295 (2013)
Update date:2022-08-15
Topics:
Qiao, Jennifer X.
Wang, Tammy C.
Ruel, Réjean
Thibeault, Carl
L'Heureux, Alexandre
Schumacher, William A.
Spronk, Steven A.
Hiebert, Sheldon
Bouthillier, Gilles
Lloyd, John
Pi, Zulan
Schnur, Dora M.
Abell, Lynn M.
Hua, Ji
Price, Laura A.
Liu, Eddie
Wu, Qimin
Steinbacher, Thomas E.
Bostwick, Jeffrey S.
Chang, Ming
Zheng, Joanna
Gao, Qi
Ma, Baoqing
McDonnell, Patricia A.
Huang, Christine S.
Rehfuss, Robert
Wexler, Ruth R.
Lam, Patrick Y. S.
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.
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