Sanderson P E, Lyle T A, Cutrona K J, Dyer D L, Dorsey B D, McDonough C M, Naylor-Olsen A M, Chen I W, Chen Z, Cook J J, Cooper C M, Gardell S J, Hare T R, Krueger J A, Lewis S D, Lin J H, Lucas B J, Lyle E A, Lynch J J, Stranieri M T, Vastag K, Yan Y, Shafer J A, Vacca J P
Departments of Antiviral Research, Biological Chemistry, Drug Metabolism, Medicinal Chemistry, Molecular Design and Diversity, Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
J Med Chem. 1998 Nov 5;41(23):4466-74. doi: 10.1021/jm980368v.
We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.
我们通过为非共价吡啶酮乙酰胺凝血酶抑制剂L-374,087（1）的3-磺酰氨基吡啶酮核心制备化学稳定的3-烷基氨基吡嗪酮生物电子等排体，解决了其在动物体内半衰期较短这一关键缺陷。化合物3（L-375,378）是1最接近的氨基吡嗪酮类似物，在大鼠、狗和猴子体内具有相当的选择性，效力略有降低，但药代动力学较1有显著改善。我们已经开发出一种高效且通用的3的合成方法，并且该化合物已被选用于进一步的临床前和临床开发。
