Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors

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• 作者：Nicholas R. Wurtz ; Brandon L. Parkhurst ; Wen Jiang ; Indawati DeLucca ; Xiaojun Zhang ; Vladimir Ladziata ; Daniel L. Cheney ; Jeffrey R. Bozarth ; Alan R. Rendina ; Anzhi Wei ; Joseph M. Luettgen ; Yiming Wu ; Pancras C. Wong ; Dietmar A. Seiffert ; Ruth R. Wexler ; E. Scott Priestley
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1077-1081
• 全文大小：363K
• ISSN：1948-5875

文摘

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(2H)-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.