Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker

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• 作者：James R. CorteTianan Fang ; Honey Osuna ; Donald J. P. Pinto ; Karen A. Rossi ; Joseph E. Myers Jr. ; Steven Sheriff ; Zhen Lou ; Joanna J. Zheng ; Timothy W. Harper ; Jeffrey M. Bozarth ; Yiming Wu ; Joseph M. Luettgen ; Dietmar A. Seiffert ; Carl P. Decicco ; Ruth R. Wexler ; Mimi L. Quan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：60
• 期：3
• 页码：1060-1075
• 全文大小：767K
• ISSN：1520-4804

文摘

A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa K_i = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC_1.5x = 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes.