Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)‑one as the P2′ Moiety

Structure–activity relationship optimization of phenylalanine P1′ and P2′ regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2′ group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine a...

Full description

Saved in:

Bibliographic Details
Published in:	ACS medicinal chemistry letters Vol. 6; no. 5; pp. 590 - 595
Main Authors:	Hu, Zilun, Wong, Pancras C, Gilligan, Paul J, Han, Wei, Pabbisetty, Kumar B, Bozarth, Jeffrey M, Crain, Earl J, Harper, Timothy, Luettgen, Joseph M, Myers, Joseph E, Ramamurthy, Vidhyashankar, Rossi, Karen A, Sheriff, Steven, Watson, Carol A, Wei, Anzi, Zheng, Joanna J, Seiffert, Dietmar A, Wexler, Ruth R, Quan, Mimi L
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 14-05-2015 American Chemical Society (ACS)
Subjects:	Amides anticoagulant factor XIa Inhibitors INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Letter Monomers Noncovalent interactions Peptides and proteins Thrombosis Thrombosis factor XIa anticoagulant
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Structure–activity relationship optimization of phenylalanine P1′ and P2′ regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2′ group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM. Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 USDOE Office of Science (SC), Basic Energy Sciences (BES) AC0206CH11357
ISSN:	1948-5875 1948-5875
DOI:	10.1021/acsmedchemlett.5b00066