Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile

Bioorg Med Chem Lett. 2013 Jan 1;23(1):90-5. doi: 10.1016/j.bmcl.2012.11.005. Epub 2012 Nov 10.

Abstract

Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Obesity Agents / chemistry*
  • Anti-Obesity Agents / pharmacokinetics
  • Anti-Obesity Agents / therapeutic use
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Half-Life
  • Mice
  • Obesity / drug therapy
  • Rats
  • Receptors, Neuropeptide Y / agonists*
  • Receptors, Neuropeptide Y / metabolism
  • Structure-Activity Relationship
  • Sulfones / chemistry*
  • Sulfones / pharmacology
  • Sulfones / therapeutic use
  • Weight Gain / drug effects

Substances

  • Anti-Obesity Agents
  • Benzimidazoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Receptors, Neuropeptide Y
  • Sulfones
  • neuropeptide Y5 receptor
  • Cytochrome P-450 Enzyme System
  • benzimidazole