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

Autor: Hu Z; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Wong PC; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Gilligan PJ; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Han W; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Pabbisetty KB; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Bozarth JM; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Crain EJ; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Harper T; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Luettgen JM; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Myers JE Jr; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Ramamurthy V; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Rossi KA; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Sheriff S; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Watson CA; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Wei A; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Zheng JJ; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Seiffert DA; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Wexler RR; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States., Quan ML; Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2015 Apr 08; Vol. 6 (5), pp. 590-5. Date of Electronic Publication: 2015 Apr 08 (Print Publication: 2015).
DOI: 10.1021/acsmedchemlett.5b00066
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: