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 2015-05, Vol.6 (5), p.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: Article
Language:English
Subjects:
Amides
anticoagulant
factor XIa
Inhibitors
INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Letter
Monomers
Noncovalent interactions
Peptides and proteins
Thrombosis
Citations: Items that this one cites
Items that cite this one
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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00066