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

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Departments of Medicinal Chemistry, Pharmacology and Lead Discovery, and Preclinical Development, Neurocrine Biosciences, 12790 El Camino Real, San Diego, California 92130
Cite this: J. Med. Chem. 2005, 48, 18, 5780–5793
Publication Date (Web):August 10, 2005
Copyright © 2005 American Chemical Society

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    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 CRF1 antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF1 binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pKi value of 8.5. Compound 12a proved to be a functional CRF1 antagonist with pIC50 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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     Department of Medicinal Chemistry.

     Department of Pharmacology and Lead Discovery.

     Department of Preclinical Development.


     To whom correspondence should be addressed. Phone:  858-617-7662. Fax:  858-617-7619. E-mail:  [email protected].

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