Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization

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• 作者：James Z. Deng ; Daniel R. McMasters ; Philippe M.A. Rabbat ; Peter D. Williams ; Craig A. Coburn ; Youwei Yan ; Lawrence C. Kuo ; S. Dale Lewis ; Bobby J. Lucas ; Julie A. Krueger et al.
• 关键词：Thrombin ; Factor Xa ; Structure-guided design
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2005
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：2005
• 卷：15
• 期：20
• 页码：4411-4416
• 文件大小：232 K

摘要

Thrombin-inhibitor X-ray crystal structures, in combination with the installation of binding elements optimized within the pyrazinone series of thrombin inhibitors, were utilized to transform a weak triazolopyrimidine lead into a series of potent oxazolopyridines. A modification intended to attenuate plasma protein binding (i.e., conversion of the P3 pyridine to a piperidine) conferred significant factor Xa activity to this series. Ultimately, these dual thrombin/factor Xa inhibitors demonstrated excellent in vitro and in vivo anticoagulant efficacy.