Sanderson P E, Cutrona K J, Dorsey B D, Dyer D L, McDonough C M, Naylor-Olsen A M, Chen I W, Chen Z, Cook J J, Gardell S J, Krueger J A, Lewis S D, Lin J H, Lucas B J, Lyle E A, Lynch J J, Stranieri M T, Vastag K, Shafer J A, Vacca J P
Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Bioorg Med Chem Lett. 1998 Apr 7;8(7):817-22. doi: 10.1016/s0960-894x(98)00117-6.
Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, Ki = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography.
将3-苄基磺酰氨基-6-甲基-2-吡啶酮乙酰胺凝血酶抑制剂L-373,890（2）的脒基哌啶P1基团用具有中等碱性的5-连接的2-氨基-6-甲基吡啶取代，得到了等活性化合物L-374,087（5，Ki = 0.5 nM）。化合物5对凝血酶的选择性远高于胰蛋白酶，在大鼠动脉血栓形成的氯化铁模型中有效，并且在犬和食蟹猴中具有口服生物利用度。通过X射线晶体学证实了5中两个甲基至关重要的结构基础。
