title: Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety.
abstract: 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.
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Zilun
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gilligan
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Kumar B
authors.initials: KB
authors.lastname: Pabbisetty
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bozarth
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Earl J
authors.initials: EJ
authors.lastname: Crain
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Harper
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Myers
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Vidhyashankar
authors.initials: V
authors.lastname: Ramamurthy
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Watson
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Anzi
authors.initials: A
authors.lastname: Wei
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Zheng
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
keywords: Thrombosis; anticoagulant; factor XIa