Summary. This SBIR Phase I proposal will set the groundwork for the clinical development of a first-in-class treatment for the long-term management of chronic hyperactivity of the hypothalamic pituitary adrenal axis (HPA) for alcohol use disorder (AUD). Therapeutics to modulate the HPA axis have been under research for decades. While glucocorticoid receptor antagonists have shown some potential in the treatment of AUD and depression, they can be counterproductive when used long-term. CRF receptor type 1 (CRF1) antagonists have also been studied extensively but have generally been unsatisfactory due to side effects and limited efficacy on the HPA. Thus, there is a considerable unmet medical need for identification of novel therapeutics to normalize HPA hyperactivity that are effective and tolerable for long-term use. HPA hyperactivity is a key pathogenic driver of AUD and a validated therapeutic target. Excessive activation of the HPA axis results in increased glucocorticoids release, which is associated with harmful consequences on the central nervous system and peripheral organs. Prolonged exposure to elevated glucocorticoids has detrimental actions on the central nervous system, causing hippocampal and prefrontal cortex functional impairments, hyper-reactivity of neural and neuroendocrine responses to stress. HPA feedback is disrupted in AUD due to overactivity. Evidence indicates that preventing excessive HPA activation will restore HPA negative feedback and reset the system at more physiological levels, reducing motivation for drinking and relapse. While the stress response is essential for survival, it can become dysregulated, contributing to the pathogenesis of a variety of illnesses, including AUD, and may result in detrimental interactions of AUD and these conditions. This Phase I SBIR proposes the lead optimization and preclinical efficacy testing of a novel candidate therapeutic aimed at the chronic management of pathologic HPA axis hyperactivity for the treatment of AUD.