Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic properties

Bioorg Med Chem Lett. 2010 Dec 15;20(24):7259-64. doi: 10.1016/j.bmcl.2010.10.095. Epub 2010 Oct 25.

Abstract

Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.

MeSH terms

  • Azabicyclo Compounds / chemical synthesis
  • Azabicyclo Compounds / chemistry*
  • Azabicyclo Compounds / pharmacokinetics
  • Humans
  • Microsomes, Liver / metabolism
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry*
  • Oxadiazoles / pharmacokinetics
  • Protein Binding
  • Pyrazoles / chemistry*
  • Pyridines / chemistry*
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism

Substances

  • Azabicyclo Compounds
  • NBI 77860
  • Oxadiazoles
  • Pyrazoles
  • Pyridines
  • Receptors, Corticotropin-Releasing Hormone
  • Recombinant Proteins
  • pyrazolopyridine