Synthesis and P1′ SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors

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• 作者：Vladimir (Uladzimir) Ladziata ; ^{vladimir.ladziata@bms.com" class="auth_mail" title="E-mail the corresponding author} ; Peter W. Glunz ; Yan Zou^&dagger ; ; Xiaojun Zhang ; Wen Jiang ; Swanee Jacutin-Porte ; Daniel L. Cheney ; Anzhi Wei ; Joseph M. Luettgen ; Timothy M. Harper ; Pancras C. Wong ; Dietmar Seiffert ; Ruth R. Wexler ; E. Scott Priestley
• 关键词：Thrombosis ; Anticoagulant ; Factor VIIa-TF inhibitor ; Macrocycle
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：26
• 期：20
• 页码：5051-5057
• 全文大小：1862 K

文摘

Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1′-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1′ group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1′ substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.