| Literature DB >> 26005539 |
Zilun Hu1, Pancras C Wong1, Paul J Gilligan1, Wei Han1, Kumar B Pabbisetty1, Jeffrey M Bozarth1, Earl J Crain1, Timothy Harper1, Joseph M Luettgen1, Joseph E Myers1, Vidhyashankar Ramamurthy1, Karen A Rossi1, Steven Sheriff1, Carol A Watson1, Anzi Wei1, Joanna J Zheng1, Dietmar A Seiffert1, Ruth R Wexler1, Mimi L Quan1.
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.Entities:
Keywords: Thrombosis; anticoagulant; factor XIa
Year: 2015 PMID： 26005539 PMCID： PMC4434461 DOI： 10.1021/acsmedchemlett.5b00066
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345