Discovery of 2-(Phenoxypyridine)-3-phenylureas as Small Molecule P2Y1 Antagonists

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• 作者：Hannguang Chao ; Huji Turdi ; Timothy F. Herpin ; Jacques Y. Roberge ; Yalei Liu ; Dora M. Schnur ; Michael A. Poss ; Robert Rehfuss ; Ji Hua ; Qimin Wu ; Laura A. Price ; Lynn M. Abell ; William A. Schumacher ; Jeffrey S. Bostwick ; Thomas E. Steinbacher ; Anne B. Stewart ; Martin L. Ogletree ; Christine S. Huang ; Ming Chang ; Angela M. Cacace ; Maredith J. Arcuri ; Deborah Celani ; Ruth R. Wexler ; R. Michael Lawrence
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 28, 2013
• 年：2013
• 卷：56
• 期：4
• 页码：1704-1714
• 全文大小：401K
• 年卷期：v.56,no.4(February 28, 2013)
• ISSN：1520-4804

文摘

Two distinct G protein-coupled purinergic receptors, P2Y₁ and P2Y₁₂, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y₁₂ blockade is well established. Recent preclinical data suggest that P2Y₁ and P2Y₁₂ inhibition provide equivalent antithrombotic efficacy, while targeting P2Y₁ has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3鈥?-(trifluoromethoxy)phenylurea, which demonstrated a 68 卤 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y₁ antagonist could potentially provide a safe and efficacious antithrombotic profile.