Lead Optimization of Therapeutic Candidates for Alcohol Use Disorder (AUD)

总结。 这项SBIR第一阶段提案将为一流的临床开发奠定基础 慢性下丘脑-垂体-肾上腺皮质功能亢进的长期治疗 AXIS(HPA)治疗酒精使用障碍(AUD)。调节HPA轴的治疗一直在进行中 几十年来的研究。虽然糖皮质激素受体拮抗剂在 治疗AUD和抑郁症，如果长期使用，可能会适得其反。CRF受体 1型(CRF1)拮抗剂也得到了广泛的研究，但总体上并不令人满意 由于HPA的副作用和疗效有限。因此，有相当大的未得到满足的医疗需求。 用于鉴定有效和可耐受的使HPA多动症正常化的新疗法 长期使用。 HPA过度活动是AUD的关键致病因素，也是有效的治疗靶点。过份 HPA轴的激活导致糖皮质激素释放增加，这与 对中枢神经系统和外周器官的有害后果。长期接触 糖皮质激素升高对中枢神经系统有不利作用，导致海马区 前额叶皮质功能损害，神经和神经内分泌的高反应性 对压力的反应。由于过度活动，AUD的HPA反馈中断。有证据表明， 防止过多的HPA激活将恢复HPA的负反馈并在 更多的生理水平，减少饮酒和复发的动机。 虽然压力反应对生存至关重要，但它可能会变得失调，从而导致 多种疾病的发病机制，包括AUD，并可能导致有害的相互作用 澳元和这些条件。这一阶段的SBIR提出了导联优化和临床前疗效 一种针对病理性HPA轴慢性治疗的新候选治疗方法的测试 治疗AUD的多动症。

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.