Discovery and evaluation of spirocyclic derivatives as antagonists of the neuropeptide Y5 receptor

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2738-43. doi: 10.1016/j.bmcl.2012.02.098. Epub 2012 Mar 6.

Abstract

A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists for the treatment of obesity. Cis and trans analogs 7a and 8a were equipotent in a Y5R binding assay (K(i)'s ≤ 1 nM) and displayed good stability in human and rat liver microsome preparations. Compound 7a failed to demonstrate weight loss activity in a diet-induced obese (DIO) rat model at unbound drug levels in the brain that exceeded the Y5R K(i) value by 25-fold over a 24-h time-period.

MeSH terms

  • Animals
  • Anti-Obesity Agents* / chemistry
  • Anti-Obesity Agents* / pharmacology
  • Cyclohexanes / pharmacology
  • Disease Models, Animal
  • Drug Discovery*
  • Drug Stability
  • Humans
  • Microsomes, Liver / drug effects
  • Molecular Structure
  • Protein Binding / drug effects
  • Pyrazoles / pharmacology
  • Rats
  • Receptors, Neuropeptide Y / antagonists & inhibitors*
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*

Substances

  • Anti-Obesity Agents
  • Cyclohexanes
  • Pyrazoles
  • Receptors, Neuropeptide Y
  • Spiro Compounds
  • neuropeptide Y5 receptor
  • spiro(cyclohexane-1,3'(1'H)-furo(3,4-C)pyridine)-4-carboxamide, N-(1-(2-fluorophenyl)-1h-pyrazol-3-yl)-1'-oxo-, trans-