1422509-95-2Relevant academic research and scientific papers
Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability
Bozarth, Jeffrey M.,Clark, Charles G.,Corte, James R.,De Lucca, Indawati,Ewing, William R.,Fang, Tianan,Harper, Timothy,Hu, Z.,Jeon, Yoon,Lam, Patrick Y. S.,Lou, Zhen,Luettgen, Joseph M.,Myers, Joseph E.,Nirschl, David S.,Orwat, Michael J.,Pinto, Donald J. P.,Rendina, Alan,Rossi, Karen A.,Seiffert, Dietmar A.,Sheriff, Steven,Smallheer, Joanne M.,Wang, Yufeng,Wexler, Ruth R.,Wu, Yiming,Xiang, Qian,Xin, Baomin,Yang, Wu,Zheng, Joanna
, (2019/08/26)
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.
CYCLIC P1 LINKERS AS FACTOR XIA INHIBITORS
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Paragraph 00311, (2013/03/26)
The present invention provides compounds of Formula (Ia): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
