Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position

…, Z Chen, RM Freidinger, AM Naylor-Olsen…

Index: Feng, Dong-Mei; Gardell, Stephen J.; Lewis, S. Dale; Bock, Mark G.; Chen, Zhongguo; Freidinger, Roger M.; Naylor-Olsen, Adel M.; Ramjit, Harri G.; Woltmann, Richard; Baskin, Elizabeth P.; Lynch, Joseph J.; Lucas, Robert; Shafer, Jules A.; Dancheck, Kimberley B.; Chen, I.-Wu; Mao, Shi-Shan; Krueger, Julie A.; Hare, Timothy R.; Mulichak, Anne M.; Vacca, Joseph P. Journal of Medicinal Chemistry, 1997 , vol. 40, # 23 p. 3726 - 3733

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Citation Number: 63

Abstract

A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b, c, e and 14d) showed nanomolar potency (K i 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F= 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel ...