Discovery of a Novel, Selective, and Orally Bioavailable Class of Thrombin Inhibitors Incorporating Aminopyridyl Moieties at the P1 Position
Journal of Medicinal Chemistry1997Vol. 40(23), pp. 3726–3733
Citations Over TimeTop 10% of 1997 papers
Dong-Mei Feng, Stephen J. Gardell, Sidney D. Lewis, Mark G. Bock, Zhongguo Chen, Roger Freidinger, Adel M. Naylor-Olsen, Harri G. Ramjit, Richard Woltmann, Elizabeth Baskin, Joseph J. Lynch, Robert J. Lucas, Jules A. Shafer, Kimberley B. Dancheck, I‐Wu Chen, Shi‐Shan Mao, Julie A. Krueger, Timothy R. Hare, A. M. Mulichak, Joseph P. Vacca
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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