Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position |
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Authors: | DM Feng SJ Gardell SD Lewis MG Bock Z Chen RM Freidinger AM Naylor-Olsen HG Ramjit R Woltmann EP Baskin JJ Lynch R Lucas JA Shafer KB Dancheck IW Chen SS Mao JA Krueger TR Hare AM Mulichak JP Vacca |
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Affiliation: | Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. |
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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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