Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability

被引：11

作者：

Clark, Charles G. ^{[1
]}

Rossi, Karen A. ^{[1
]}

Corte, James R. ^{[1
]}

Fang, Tianan ^{[1
]}

Smallheer, Joanne M. ^{[1
]}

De Lucca, Indawati ^{[1
]}

Nirschl, David S. ^{[1
]}

Orwat, Michael J. ^{[1
]}

Pinto, Donald J. P. ^{[1
]}

Hu, Zilun ^{[1
]}

Wang, Yufeng ^{[1
]}

Yang, Wu ^{[1
]}

Jeon, Yoon ^{[1
]}

Ewing, William R. ^{[1
]}

Myers, Joseph E., Jr. ^{[1
]}

Sheriff, Steven ^{[1
]}

Lou, Zhen ^{[1
]}

Bozarth, Jeffrey M. ^{[1
]}

Wu, Yiming ^{[1
]}

Rendina, Alan ^{[1
]}

Harper, Timothy ^{[1
]}

Zheng, Joanna ^{[1
]}

Xin, Baomin ^{[1
]}

Xiang, Qian ^{[1
]}

Luettgen, Joseph M. ^{[1
]}

Seiffert, Dietmar A. ^{[1
]}

Wexler, Ruth R. ^{[1
]}

Lam, Patrick Y. S. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, POB 4000, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 19期

关键词：

Factor XIa inhibitors; FXIa; Activated partial thromboplastin time; aPTT; Thrombosis; Anticoagulant; Bioavailability; COAGULATION-FACTOR XIA; SMALL-MOLECULE; BLEEDING-TIME; DISEASE; POTENT;

D O I：

10.1016/j.bmcl.2019.08.008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.

引用

页数：7

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