Tucker T J, Brady S F, Lumma W C, Lewis S D, Gardell S J, Naylor-Olsen A M, Yan Y, Sisko J T, Stauffer K J, Lucas B J, Lynch J J, Cook J J, Stranieri M T, Holahan M A, Lyle E A, Baskin E P, Chen I W, Dancheck K B, Krueger J A, Cooper C M, Vacca J P
Departments of Medicinal Chemistry, Biological Chemistry, Pharmacology, Drug Metabolism, and Molecular Design and Diversity, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
J Med Chem. 1998 Aug 13;41(17):3210-9. doi: 10.1021/jm9801713.
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.
作为制备具有治疗用途的口服活性凝血酶抑制剂的持续努力的一部分，我们合成了一系列在P1位使用非碱性基团的化合物。这项工作基于我们先前报道的先导结构化合物1，它是通过基于树脂的方法对P1进行变化而发现的。通过最小化P3基团的大小和亲脂性，并在N端或P1芳环的2位引入氢键基团，我们制备了该系列中的许多衍生物，它们表现出亚纳摩尔级的酶活性，同时具有良好的体内抗血栓形成和生物利用度特征。氧乙酸酰胺化合物14b表现出最佳的体外和体内活性总体特征，晶体学研究表明其在凝血酶活性位点具有独特的结合模式。
