Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors

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• 作者：Jeremy M. Richter ; Daniel L. Cheney ; J. Alex Bates ; Anzhi Wei ; Joseph M. Luettgen ; Alan R. Rendina ; Timothy M. Harper ; Rangaraj Narayanan ; Pancras C. Wong ; Dietmar Seiffert ; Ruth R. Wexler ; E. Scott Priestley
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：8
• 期：1
• 页码：67-72
• 全文大小：358K
• ISSN：1948-5875

文摘

Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa K_i was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.