Synthesis and evaluation of carbamate and aryl ether substituted pyrazinones as corticotropin releasing factor-1 (CRF₁) receptor antagonists

Bioorg Med Chem Lett. 2016 May 1;26(9):2184-7. doi: 10.1016/j.bmcl.2016.03.067. Epub 2016 Mar 17.

Abstract

A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.9 nM). The synthesis, structure-activity relationships and in vitro metabolic stability properties of compounds in this series will be described.

Keywords: CRF; CRF1 receptor antagonists; Depression; Neuroscience; Pyrazinones.

Publication types

  • Letter

MeSH terms

  • Animals
  • Carbamates / chemical synthesis
  • Carbamates / metabolism
  • Carbamates / pharmacology*
  • Cell Line, Tumor
  • Humans
  • Microsomes, Liver / metabolism
  • Pyrazines / chemical synthesis
  • Pyrazines / metabolism
  • Pyrazines / pharmacology*
  • Rats
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Carbamates
  • Pyrazines
  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1