Design and Synthesis of Tricyclic Corticotropin-Releasing Factor-1 Antagonists

Autor: Charles Q. Huang, James R. McCarthy, Paul D. Crowe, Raymond S. Gross, John Saunders, Dimitri E. Grigoriadis, Jodene Nelson, Richard Lowe, Brian Dyck, John P. Williams, Dragan Marinkovic, Sam R. J. Hoare, Tim Coon, Robert W. Sullivan, Mustapha Haddach, Said Zamani-Kord, Manisha Moorjani, Zhiqiang Guo, Jane Han Bu, Takung Chen
Rok vydání: 2005
Předmět:
Zdroj: Journal of Medicinal Chemistry. 48:5780-5793
ISSN: 1520-4804
0022-2623
DOI: 10.1021/jm049085v
Popis: 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.
Databáze: OpenAIRE