Combinatorial Organic Synthesis of a CRF-R Antagonist

Corticotropin releasing factor (CRF), a 41 amino acid peptide, controls the anterior pituitarysecretion of adrenocorticotropin and other proopiomelanocortin products. CRF also coordinates theendocrine, behavioral and autonomic responses to stress. Considerable evidence exists from studies ofcerebrospinal fluid, postmortem tissue receptor measurements, and CRF stimulation tests to support thehypothesis that CRF is hypersecreted in clinically depressed patients. There is also evidence for aninvolvement of CRF in the pathophysiology of anxiety disorders and in the mechanism of action ofbenzodiazepine and non-benzodiazepine anxiolytics. We have developed proprietary small moleculeCRF-receptor antagonists. This research will sytematically delineate the important structuralcharacteristics of these molecules which are responsible for binding to the CRF receptor, and to discoveradditional derivatives. Combinatorial libraries of small molecule analogues will be prepared andinvestigated for their in vitro potency at the human CRF-receptor. The recent cloning of the human CRFreceptor allows for novel biological assay formats to be developed which will greatly enhance theidentification of novel, small molecule orally active drugs for the treatment of depression and anxietydisorders.