2. Academic Validation
  3. Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists

Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists

  • J Med Chem. 2005 Sep 8;48(18):5780-93. doi: 10.1021/jm049085v.
Raymond S Gross 1,  Zhiqiang Guo,  Brian Dyck,  Tim Coon,  Charles Q Huang,  Richard F Lowe,  Dragan Marinkovic,  Manisha Moorjani,  Jodene Nelson,  Said Zamani-Kord,  Dimitri E Grigoriadis,  Sam R J Hoare,  Paul D Crowe,  Jane Han Bu,  Mustapha Haddach,  James McCarthy,  John Saunders,  Robert Sullivan,  Takung Chen,  John P Williams
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, California 92130, USA.
PMID: 16134945 DOI: 10.1021/jm049085v
Abstract

Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF(1) antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF(1) binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pK(i) value of 8.5. Compound 12a proved to be a functional CRF(1) antagonist with pIC(50) values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo.

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