Discovery of highly potent and efficacious MC4R agonists with spiroindane N-Me-1,2,4-triazole privileged structures for the treatment of obesity

Bioorg Med Chem Lett. 2010 Nov 15;20(22):6524-32. doi: 10.1016/j.bmcl.2010.09.049. Epub 2010 Sep 19.

Abstract

We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.

MeSH terms

  • Animals
  • Chromatography, High Pressure Liquid
  • Disease Models, Animal
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Obesity / drug therapy*
  • Rats
  • Receptor, Melanocortin, Type 4 / agonists*
  • Receptor, Melanocortin, Type 4 / genetics
  • Structure-Activity Relationship
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use

Substances

  • Receptor, Melanocortin, Type 4
  • Triazoles