Discovery of a Novel, Selective, and Orally Bioavailable Class of Thrombin Inhibitors Incorporating Aminopyridyl Moieties at the P1 Position
Dong-Mei Feng(United States Military Academy), Stephen J. Gardell(United States Military Academy), Sidney D. Lewis(United States Military Academy), Mark G. Bock(United States Military Academy), Zhongguo Chen(United States Military Academy), Roger Freidinger(United States Military Academy), Adel M. Naylor-Olsen(United States Military Academy), Harri G. Ramjit(United States Military Academy), Richard Woltmann(United States Military Academy), Elizabeth Baskin(United States Military Academy), Joseph J. Lynch(United States Military Academy), Robert J. Lucas(United States Military Academy), Jules A. Shafer(United States Military Academy), Kimberley B. Dancheck(United States Military Academy), I‐Wu Chen(United States Military Academy), Shi‐Shan Mao(United States Military Academy), Julie A. Krueger(United States Military Academy), Timothy R. Hare(United States Military Academy), A. M. Mulichak(United States Military Academy), Joseph P. Vacca(United States Military Academy)
Cited by 57Open Access
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 (Ki 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 aminopyridyl group at P1 was a key step in our search for a clinical candidate.
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