8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists

J Med Chem. 2009 May 14;52(9):3073-83. doi: 10.1021/jm9000242.

Abstract

This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 4.7 +/- 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / chemistry
  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-Anxiety Agents / pharmacology
  • Anti-Anxiety Agents / therapeutic use
  • Anxiety / drug therapy
  • Clinical Trials as Topic
  • Dogs
  • Female
  • Inhibitory Concentration 50
  • Male
  • Rats
  • Receptors, Biogenic Amine / metabolism
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Triazines / chemistry*
  • Triazines / pharmacokinetics
  • Triazines / pharmacology*
  • Triazines / therapeutic use

Substances

  • Anti-Anxiety Agents
  • Receptors, Biogenic Amine
  • Receptors, Corticotropin-Releasing Hormone
  • Triazines
  • CRF receptor type 1