Identification and hit-to-lead optimization of a novel class of CB1 antagonists

Bioorg Med Chem Lett. 2010 Sep 15;20(18):5449-53. doi: 10.1016/j.bmcl.2010.07.091. Epub 2010 Jul 25.

Abstract

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

MeSH terms

  • Animals
  • Benzimidazoles / chemistry*
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Humans
  • Hypothermia / chemically induced
  • Hypothermia / drug therapy
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Male
  • Mice
  • Microsomes, Liver / metabolism
  • Obesity / drug therapy
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Solubility
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Indoles
  • Receptor, Cannabinoid, CB1
  • indole
  • benzimidazole