Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability

Bioorg Med Chem. 2014 Jul 1;22(13):3515-26. doi: 10.1016/j.bmc.2014.04.023. Epub 2014 Apr 20.

Abstract

In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition.

Keywords: Benzimidazole; Imidazopyridine; Metabolic stability; PDE10A inhibitor; Schizophrenia.

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Phosphodiesterase Inhibitors
  • Recombinant Proteins
  • benzimidazole
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases