2. Academic Validation
  3. Synthesis and structure-activity relationships of 8-(pyrid-3-yl)pyrazolo[1,5-a]-1,3,5-triazines: potent, orally bioavailable corticotropin releasing factor receptor-1 (CRF1) antagonists

Synthesis and structure-activity relationships of 8-(pyrid-3-yl)pyrazolo[1,5-a]-1,3,5-triazines: potent, orally bioavailable corticotropin releasing factor receptor-1 (CRF1) antagonists

  • J Med Chem. 2009 May 14;52(9):3084-92. doi: 10.1021/jm900025h.
Paul J Gilligan 1,  Todd Clarke,  Liqi He,  Snjezana Lelas,  Yu-Wen Li,  Karen Heman,  Lawrence Fitzgerald,  Keith Miller,  Ge Zhang,  Anne Marshall,  Carol Krause,  John F McElroy,  Kathyrn Ward,  Kim Zeller,  Harvey Wong,  Steven Bai,  Joanne Saye,  Scott Grossman,  Robert Zaczek,  Stephen P Arneric,  Paul Hartig,  David Robertson,  George Trainor
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Co., 311 Pennington-Rocky Hill Road, Hopewell, New Jersey 08540, USA. [email protected]
PMID: 19361209 DOI: 10.1021/jm900025h
Abstract

This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. These CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.

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