Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup

Bioorg Med Chem Lett. 2015 Jul 15;25(14):2793-9. doi: 10.1016/j.bmcl.2015.05.008. Epub 2015 May 15.

Abstract

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.

Keywords: Dihydropyrrolopyrazolones; MCHR1 receptor antagonists; Obesity; Off-rates.

MeSH terms

  • Animals
  • Anti-Obesity Agents / chemistry*
  • Anti-Obesity Agents / pharmacokinetics
  • Anti-Obesity Agents / pharmacology
  • Anti-Obesity Agents / therapeutic use
  • Half-Life
  • Humans
  • Obesity / drug therapy
  • Protein Binding
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Somatostatin / antagonists & inhibitors*
  • Receptors, Somatostatin / metabolism
  • Structure-Activity Relationship
  • Weight Loss / drug effects

Substances

  • Anti-Obesity Agents
  • MCHR1 protein, human
  • Pyrazoles
  • Receptors, Somatostatin
  • pyrazole