Design and synthesis of novel benzimidazole derivatives as phosphodiesterase 10A inhibitors with reduced CYP1A2 inhibition

Bioorg Med Chem. 2013 Dec 15;21(24):7612-23. doi: 10.1016/j.bmc.2013.10.035. Epub 2013 Oct 31.

Abstract

A novel class of phosphodiesterase 10A (PDE10A) inhibitors with reduced CYP1A2 inhibition were designed and synthesized starting from 2-{[(1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (1). Introduction of an isopropyl group at the 2-position and a methoxy group at the 5-position of the benzimidazole ring of lead compound 1 resulted in the identification of 2-{[(2-isopropyl-5-methoxy-1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (25b), which exhibited potent PDE10A inhibitory activity with reduced CYP1A2 inhibitory activity compared to compound 1.

Keywords: Benzimidazole; CYP1A2; PDE10A inhibitor; Schizophrenia.

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Crystallography, X-Ray
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP1A2 Inhibitors*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • 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
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Phosphodiesterase Inhibitors
  • Recombinant Proteins
  • benzimidazole
  • CYP1A2 protein, human
  • Cytochrome P-450 CYP1A2
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases