Identification Of 1-Methyl-N-(Propan-2-Yl)-N-({2-[4-(Trifluoromethoxy)Phenyllpyridin-4-Yl} Methyl)-1h-Imidazole-4-Carboxamide As A Potent And Orally Available Glycine Transporter 1 Inhibitor

We previously identified 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (5, TP0439150) as a potent and orally available glycine transporter 1 (GlT1) inhibitor. In this article, we describe our identification of 1-methyl-N-(propan-2-yl)-N-({2[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1H-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.