SBIR-STTR Award

Corticotropin-releasing factor (CRF), a 41-amino acid peptide, acting at specific receptors in the brain and pituitary has been demonstrated to initiate behavioral, physiological and neuroendocrine responses that mimic the response to stress in animals. In addition to its physiological role in mediating stress, recent clinical studies have provided evidence to suggest that hyperactivity of CRF-containing pathways within the brain may be a contributing pathophysiologic factor in depressive disorders Hypersecretion and/or hyperproduction of CRF has also been implicated in a number of other stress-related disorders including anxiety, stress-induce cardiovascular abnormalities, anorexia nervosa and irritable bowel syndrome. The current proposal provides a plan for identification and evaluation of centrally-active nonpeptide antagonists of CRF to be developed as novel therapeutic approaches for treating any of the disorders mentioned above. Starting with an inventory of approximately 20,000 compounds, in vitro radioligand binding and adenylate cyclase assays will serve as initial screening procedures for identifying selective CRF antagonists. Lead structures will then be evaluated for CRF-antagonist activity in vivo using both behavioral and cardiovascular monitoring. Finally, CRF- antagonists will be evaluated for anxiolytic potential in a battery of behavioral tests. Compounds identified during Phase I studies will provid points of departure for synthetic chemical improvements during Phase II work with continued evaluation of compounds for anxiolytic activity as wel as the development of additional animal models to assess other potential therapeutic uses for a CRF antagonist. National Institute of Mental Health (NIMH)

Substantial evidence has accumulated from basic science and clinical studies implicating Corticotropin-releasing factor (CRF) as a physiological or pathophysiological mediator of stress responses of stress-induced disorders. Therefore, it has been hypothesized that a centrally-active CRF antagonist would represent a novel approach for treating anxiety and affective disorders as well as a range of other diseases which are directly associated with or exacerbated by stress. Phase I efforts resulted in the identification of four structurally- distinct nonpeptide compounds exhibiting an in vitro profile indicative of selective CRF antagonism. In vivo evaluation of "lead" compounds and close structural analogs evidence of blockade of actions of exogenously administered CRF. Several of these compounds had an anxiolytic profile in behavioral models. Based on these results, the Phase II proposal seeks to continue and expand upon Phase I efforts by (1) increasing synthetic chemistry effort with a goal of improving the pharmacological profile of the lead structures, (2) examining new compound libraries for additional chemical leads (3) employing receptor binding and in vivo testing approaches of Phase I for evaluation of new compounds and (4) developing additional animal models to further characterize the therapeutic potential of CRF antagonists. It is hoped that compounds will be identified during the Phase II period that would have substantial potential for clinical development.

Thesaurus Terms:
Chemical Structure--Biological Activity, Drugs Synthesis, Design And Production, Drugs, Pharmacology, Antagonists, Pituitary-Diencephalon Hormones, Acth Releasing Factor, Receptors, Hormone Receptors Adrenal Cortex Hormones, Corticosterone, Drugs Screening And Evaluation, Gastrointestinal Disorders, Colon Disorders, Irritable Bowel Syndrome, Immunity, Immunosuppression, Models, Disease Models, Nucleotidyl-Cyclases, Adenylate Cyclase, Pituitary-Diencephalon Hormones, Acth, Psychology, Behavior Animal, Psychopharmacological Agents, Antidepressants, Psychopharmacological Agents, Tranquilizers, Pyrazoles, Receptor Binding, Stress Animals, Chordates, Mammals, Rodents, Myomorpha, Mice (Laboratory), Animals, Chordates, Mammals, Rodents, Myomorpha, Rats (Laboratory)