Conformationally Constrained ortho-Anilino Diaryl Ureas: Discovery of 1-(2-(1鈥?Neopentylspiro[indoline-3,4鈥?piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a Potent, Selective, and

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• 作者：Jennifer X. Qiao ; Tammy C. Wang ; R茅jean Ruel ; Carl Thibeault ; Alexandre L鈥橦eureux ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9275-9295
• 全文大小：956K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

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.