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.
