Identification of 1-Methyl-N-(propan-2-yl)-N-({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1H-imidazole-4-carboxamide as a Potent and Orally Available Glycine Transporter 1 Inhibitor

摘要

We previously identified 3-chloro- N -{( S )-[3-(1-ethyl-1 H -pyrazol-4-yl)phenyl][(2 S )-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide ( 5 , TP0439150) as a potent and orally available glycine transporter 1 (GlyT1) inhibitor. In this article, we describe our identification of 1-methyl- N -(propan-2-yl)- N -({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1 H -imidazole-4-carboxamide ( 7n ) as a structurally diverse back-up compound of 5 , using central nervous system multiparameter optimization (CNS MPO) as a drug-likeness guideline. Compound 7n showed a higher CNS MPO score and different physicochemical properties as compared to 5 . Compound 7n exhibited potent GlyT1 inhibitory activity, a favorable pharmacokinetics profile, and elicited an increase in the cerebrospinal fluid (CSF) concentration of glycine in rats.