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

Chem Pharm Bull (Tokyo). 2016;64(11):1630-1640. doi: 10.1248/cpb.c16-00610.

Abstract

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 (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)-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.

MeSH terms

  • Administration, Oral
  • Animals
  • Cerebrospinal Fluid / chemistry*
  • Cerebrospinal Fluid / metabolism
  • Dose-Response Relationship, Drug
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Molecular Structure
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • 1-methyl-N-(propan-2-yl)-N-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methyl)-1H-imidazole-4-carboxamide
  • Glycine Plasma Membrane Transport Proteins
  • Imidazoles
  • Pyridines
  • SLC6A9 protein, human