P 2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold

…, SD Lewis, BJ Lucas, JA Krueger, C Miller-Stein…

Index: Nantermet, Philippe G.; Burgey, Christopher S.; Robinson, Kyle A.; Pellicore, Janetta M.; Newton, Christina L.; Deng, James Z.; Selnick, Harold G.; Lewis, S. Dale; Lucas, Bobby J.; Krueger, Julie A.; Miller-Stein, Cynthia; White, Rebecca B.; Wong, Bradley; McMasters, Daniel R.; Wallace, Audrey A.; Lynch Jr., Joseph J.; Yan, Youwei; Chen, Zhongguo; Kuo, Lawrence; Gardell, Stephen J.; Shafer, Jules A.; Vacca, Joseph P.; Lyle, Terry A. Bioorganic and Medicinal Chemistry Letters, 2005 , vol. 15, # 11 p. 2771 - 2775

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Citation Number: 17

Abstract

In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2- aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P1 benzylamide delivered the potent thrombin inhibitor 21 (Ki= ...