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

酒精使用障碍 (AUD) 治疗候选药物的先导优化

• 批准号: 10547026
• 负责人: Linda S Lloyd
• 金额: $ 25.77万
• 依托单位: STRESS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547026
• 关键词: Address; Adherence; Affinity; Antibodies; Automobile Driving; Blood Circulation; Chronic; Clinical; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Dose; Drug Kinetics; Ethers; Excision; Experimental Designs; Exposure to; Feedback; Follow-Up Studies; Foundations; Glucocorticoid Receptor; Glucocorticoids; Half-Life; Heavy Drinking; Hippocampus (Brain); Hormones; Human; Hyperactivity; In Vitro; Injections; Interferometry; Investigational Drugs; Lead; Left; Medical; Mental Depression; Modeling; Monitor; Monoclonal Antibodies; Motivation; Mus; Neuraxis; Neurosecretory Systems; Organ; Oryctolagus cuniculus; Pathogenesis; Pathogenicity; Pathologic; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Pituitary Gland; Plasma; Predisposition; Prefrontal Cortex; Primates; Recombinant Antibody; Recombinants; Relapse; Research; Rodent Model; Safety; Serum; Small Business Innovation Research Grant; Stress; System; Testing; Therapeutic; Therapeutic Uses; Therapeutic antibodies; Transgenic Mice; Variant; alcohol abuse therapy; alcohol seeking behavior; alcohol use disorder; antagonist; behavior measurement; biological adaptation to stress; blood pressure reduction; clinical development; corticotropin releasing factor-binding protein; design; drinking; efficacy study; efficacy testing; functional disability; humanized antibody; hypothalamic-pituitary-adrenal axis; in vivo; lead optimization; mouse model; novel; novel therapeutics; preclinical efficacy; prevent; relating to nervous system; response; restraint stress; side effect; small molecule; social defeat; therapeutic candidate; therapeutic target

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.

概括。 SBIR I期提案将为第一类的临床发展树立基础 用于长期管理下丘脑垂体肾上腺的慢性多动症的治疗 轴（HPA）用于饮酒障碍（AUD）。调节HPA轴的治疗疗法已在 数十年来的研究。糖皮质激素受体拮抗剂在 aud和抑郁症的治疗，长期使用时它们可能会适得其反。 CRF受体 1型（CRF1）拮抗剂也经过广泛研究，但通常不令人满意 由于副作用和对HPA的功效有限。因此，有很大的未满足医疗需求 用于鉴定新型治疗剂以使HPA多动症的正常化均高效和可耐受性 供长期使用。 HPA多动症是AUD的关键致病驱动力和经过验证的治疗靶标。过多的 HPA轴的激活导致糖皮质激素释放增加，这与 对中枢神经系统和周围器官的有害后果。长时间接触 升高的糖皮质激素对中枢神经系统有不利的作用，导致海马 和前额叶皮层功能障碍，神经和神经内分泌的过度反应性 对压力的反应。由于过度活动，HPA反馈在AUD中被破坏。证据表明 防止过度HPA激活将恢复HPA负面反馈并重置系统 更多的生理水平，减少饮酒和复发的动力。 虽然压力反应对于生存至关重要，但可能会失调，有助于 各种疾病的发病机理，包括AUD，并可能导致有害的相互作用 aud和这些条件。该阶段I SBIR提出了铅优化和临床前功效 针对病理HPA轴长期管理的新型候选治疗方法的测试 用于治疗AUD的多动症。