Wurtz Nicholas R, Parkhurst Brandon L, Jiang Wen, DeLucca Indawati, Zhang Xiaojun, Ladziata Vladimir, Cheney Daniel L, Bozarth Jeffrey R, Rendina Alan R, Wei Anzhi, Luettgen Joseph M, Wu Yiming, Wong Pancras C, Seiffert Dietmar A, Wexler Ruth R, Priestley E Scott
Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell Township, New Jersey 08540, United States.
Bristol-Myers Squibb R&D , 311 Pennington Rocky Hill Road, Pennington, New Jersey 08534, United States.
ACS Med Chem Lett. 2016 Sep 17;7(12):1077-1081. doi: 10.1021/acsmedchemlett.6b00282. eCollection 2016 Dec 8.
Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.
凝血因子 VIIa（FVIIa）是凝血级联反应中的一种丝氨酸蛋白酶，其抑制剂在临床前血栓形成模型中显示出强大的抗血栓疗效，且出血风险极小。然而，由于已知的化学类型需要在 S1 结合口袋中有一个高度碱性的基团以实现高亲和力，因此发现强效、口服活性的 FVIIa 抑制剂在很大程度上并不成功。最近报道的一项片段筛选工作发现了一种中性杂环化合物——7-氯-3,4-二氢异喹啉-1(2)-酮，它能结合在 FVIIa 的 S1 口袋中，并可被纳入苯基甘氨酸 FVIIa 抑制剂中。对这个 P1 结合基团的优化产生了第一批具有低纳摩尔效力的中性、可渗透的 FVIIa 抑制剂。
