Discovery of diarylurea P2Y₁ antagonists with improved aqueous solubility

详细信息    查看全文

• 作者：Tammy C. Wang ; Jennifer X. Qiao ; ^{jennifer.qiao@bms.com} ; Charles G. Clark ; Ji Jua ; Laura A. Price ; Qimin Wu ; Ming Chang ; Joanna Zheng ; Christine S. Huang ; Gerry Everlof ; William A. Schumacher ; Pancras C. Wong ; Dietmar A. Seiffert ; Anne B. Stewart ; Jeffrey S. Bostwick ; Earl J. Crain ; Carol A. Watson ; Robert Rehfuss ; Ruth R. Wexler ; Patrick Y.S. Lam^&dagger ;
• 关键词：P2Y1 antagonists ; Diarylurea ; Structure&ndash ; activity relationship (SAR) ; Aqueous solubility ; In vivo efficacy/bleeding model
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 June, 2013
• 年：2013
• 卷：23
• 期：11
• 页码：3239-3243
• 全文大小：2294 K

文摘

Preclinical data suggests that P2Y₁ antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y₁₂ antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y₁ antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.