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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.

SUBMITTER: Hu Z

PROVIDER: S-EPMC4434461 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Hu Zilun Z Wong Pancras C PC Gilligan Paul J PJ Han Wei W Pabbisetty Kumar B KB Bozarth Jeffrey M JM Crain Earl J EJ Harper Timothy T Luettgen Joseph M JM Myers Joseph E JE Ramamurthy Vidhyashankar V Rossi Karen A KA Sheriff Steven S Watson Carol A CA Wei Anzi A Zheng Joanna J JJ Seiffert Dietmar A DA Wexler Ruth R RR Quan Mimi L ML

ACS medicinal chemistry letters 20150408 5

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 a ...[more]

PMID: 26005539

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Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives.

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| S-EPMC10473006 | biostudies-literature

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