Design, synthesis and identification of novel benzimidazole derivatives as highly potent NPY Y5 receptor antagonists with attractive in vitro ADME profiles

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5498-502. doi: 10.1016/j.bmcl.2012.07.020. Epub 2012 Jul 14.

Abstract

Optimization of our HTS hit 1, mainly focused on modification at the C-2 position of the benzimidazole core, is described. Elimination of the flexible and metabolically labile -S-CH(2)- part and utilization of less lipophilic pyridone substructure led to identification of novel NPY Y5 receptor antagonists 6, which have low to sub-nanomolar Y5 receptor binding affinity with improved CYP450 inhibition profiles, good solubilities and high metabolic stabilities.

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology*
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Design
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Obesity / drug therapy
  • Pyridones / chemical synthesis
  • Pyridones / chemistry*
  • Pyridones / metabolism
  • Pyridones / pharmacology*
  • Rats
  • Receptors, Neuropeptide Y / antagonists & inhibitors*
  • Receptors, Neuropeptide Y / metabolism

Substances

  • Benzimidazoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Pyridones
  • Receptors, Neuropeptide Y
  • neuropeptide Y5 receptor
  • Cytochrome P-450 Enzyme System