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

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.