Pyrrolo[1,2-b]pyridazines, pyrrolo[2,1-f]triazin-4(3H)-ones, and related compounds as novel corticotropin-releasing factor 1 (CRF₁) receptor antagonists

Bioorg Med Chem. 2012 Jan 15;20(2):1122-38. doi: 10.1016/j.bmc.2011.11.015. Epub 2011 Dec 3.

Abstract

To identify structurally novel corticotropin-releasing factor 1 (CRF(1)) receptor antagonists, a series of bicyclic core analogs pyrrolo[1,2-b]pyridazines and pyrrolo[2,1-f]triazin-4(3H)-ones, which were designed based on a monocyclic core antagonist, was synthesized and evaluated. Among the compounds tested, 2-difluoromethoxy-4-methylpyridin-5-yl analog 27 was found to show efficacy in a dose-dependent manner in an elevated plus maze test in rats. The discovery process and structure-activity relationship is presented.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / chemical synthesis
  • Anti-Anxiety Agents / chemistry*
  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-Anxiety Agents / pharmacology*
  • CRF Receptor, Type 1
  • Male
  • Protein Binding / drug effects
  • Pyridazines / chemistry*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Structure-Activity Relationship
  • Triazines / chemical synthesis
  • Triazines / chemistry*
  • Triazines / pharmacokinetics
  • Triazines / pharmacology*

Substances

  • Anti-Anxiety Agents
  • Pyridazines
  • Receptors, Corticotropin-Releasing Hormone
  • Triazines
  • CRF Receptor, Type 1