Discovery and evaluation of pyrazolo[1,5-a]pyrimidines as neuropeptide Y1 receptor antagonists

Bioorg Med Chem Lett. 2011 May 1;21(9):2641-5. doi: 10.1016/j.bmcl.2010.12.116. Epub 2011 Jan 7.

Abstract

A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H-pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents.

MeSH terms

  • Animals
  • Appetite Depressants / pharmacology
  • Blood Pressure / drug effects
  • Drug Discovery*
  • Eating / drug effects*
  • Humans
  • Mice
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrazolones / chemical synthesis
  • Pyrazolones / chemistry
  • Pyrazolones / pharmacology
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Neuropeptide Y / antagonists & inhibitors*

Substances

  • Appetite Depressants
  • CP 671906
  • Pyrazoles
  • Pyrazolones
  • Pyridines
  • Pyrimidines
  • Receptors, Neuropeptide Y