Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies

Bioorg Med Chem Lett. 2015 Oct 15;25(20):4412-8. doi: 10.1016/j.bmcl.2015.09.018. Epub 2015 Sep 8.

Abstract

Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.

Keywords: Anti-obesity; Biliary toxicity; Metabolite toxicity; Non-basic MCHR1 antagonists; Off-rates.

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Rats
  • Receptors, Somatostatin / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Triazines / administration & dosage
  • Triazines / chemistry
  • Triazines / pharmacology*

Substances

  • MCHR1 protein, human
  • Receptors, Somatostatin
  • Triazines
  • azolotriazinone