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

…, SD Lewis, BJ Lucas, JA Krueger, B Strulovici…

Index: Deng, James Z.; McMasters, Daniel R.; Rabbat, Philippe M.A.; Williams, Peter D.; Coburn, Craig A.; Yan, Youwei; Kuo, Lawrence C.; Lewis, S. Dale; Lucas, Bobby J.; Krueger, Julie A.; Strulovici, Berta; Vacca, Joseph P.; Lyle, Terry A.; Burgey, Christopher S. Bioorganic and Medicinal Chemistry Letters, 2005 , vol. 15, # 20 p. 4411 - 4416

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Citation Number: 28

Abstract

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 (ie, conversion of the P3 pyridine to a piperidine) conferred significant factor Xa activity to this series. Ultimately, these dual ...