Discovery and structure-activity relationship of a novel spirocarbamate series of NPY Y5 antagonists

Bioorg Med Chem Lett. 2010 Oct 15;20(20):6103-7. doi: 10.1016/j.bmcl.2010.08.041. Epub 2010 Aug 12.

Abstract

A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3mg/kg po.

MeSH terms

  • Animals
  • Carbamates / chemistry*
  • Carbamates / metabolism
  • Carbamates / pharmacokinetics
  • Carbamates / pharmacology*
  • Cell Line
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Humans
  • Microsomes, Liver / metabolism
  • Rats
  • Receptors, Neuropeptide Y / antagonists & inhibitors*
  • Receptors, Neuropeptide Y / metabolism*
  • Spiro Compounds / chemistry*
  • Spiro Compounds / metabolism
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Carbamates
  • Cytochrome P-450 Enzyme Inhibitors
  • Receptors, Neuropeptide Y
  • Spiro Compounds
  • Cytochrome P-450 Enzyme System