Design, synthesis, binding and docking-based 3D-QSAR studies of 2-pyridylbenzimidazoles--a new family of high affinity CB1 cannabinoid ligands

Molecules. 2013 Apr 4;18(4):3972-4001. doi: 10.3390/molecules18043972.

Abstract

A series of novel 2-pyridylbenzimidazole derivatives was rationally designed and synthesized based on our previous studies on benzimidazole 14, a CB1 agonist used as a template for optimization. In the present series, 21 compounds displayed high affinities with Ki values in the nanomolar range. JM-39 (compound 39) was the most active of the series (KiCB1 = 0.53 nM), while compounds 31 and 44 exhibited similar affinities to WIN 55212-2. CoMFA analysis was performed based on the biological data obtained and resulted in a statistically significant CoMFA model with high predictive value (q2 = 0.710, r2 = 0.998, r2pred = 0.823).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacology*
  • Benzoxazines / chemistry
  • Cannabinoids / chemistry*
  • Humans
  • Ligands
  • Models, Biological
  • Morpholines / chemistry
  • Naphthalenes / chemistry
  • Protein Conformation
  • Quantitative Structure-Activity Relationship
  • Receptor, Cannabinoid, CB1 / metabolism*

Substances

  • 2-(2'-pyridyl)benzimidazole
  • Benzimidazoles
  • Benzoxazines
  • Cannabinoids
  • Ligands
  • Morpholines
  • Naphthalenes
  • Receptor, Cannabinoid, CB1
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone