发现一类新型、选择性且口服生物可利用的凝血酶抑制剂，其在P1位含有氨基吡啶基部分。
Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position.
作者信息
Feng D M, Gardell S J, Lewis S D, Bock M G, Chen Z, Freidinger R M, Naylor-Olsen A M, Ramjit H G, Woltmann R, Baskin E P, Lynch J J, Lucas R, Shafer J A, Dancheck K B, Chen I W, Mao S S, Krueger J A, Hare T R, Mulichak A M, Vacca J P
机构信息
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
出版信息
J Med Chem. 1997 Nov 7;40(23):3726-33. doi: 10.1021/jm970493r.
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.
已发现一类新型的凝血酶抑制剂，其在P1位含有氨基吡啶部分。其中四种凝血酶抑制剂（13b、c、e和14d）表现出纳摩尔级别的效力（Ki为0.8 - 12 nM），与胰蛋白酶相比，对凝血酶具有300 - 1500倍的选择性，并且在大鼠或犬类中具有良好的口服生物利用度（F = 40 - 76%）。中性的P1有望提高代谢稳定性和口服吸收。在P1位鉴定出这种新型氨基吡啶基团是我们寻找临床候选药物的关键一步。
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