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。 该 SBIR 第一阶段提案将为一流的临床开发奠定基础 下丘脑垂体肾上腺慢性机能亢进症的长期治疗 酒精使用障碍 (AUD) 轴 (HPA)。调节 HPA 轴的治疗方法已在研究中 研究了几十年。虽然糖皮质激素受体拮抗剂在 治疗AUD和抑郁症，长期使用可能会适得其反。 CRF受体 1 型 (CRF1) 拮抗剂也已得到广泛研究，但总体效果并不令人满意 由于 HPA 的副作用和功效有限。因此，存在相当大的未满足的医疗需求 确定有效且可耐受的新疗法，使 HPA 过度活跃正常化 供长期使用。 HPA 过度活跃是 AUD 的关键致病驱动因素，也是经过验证的治疗靶点。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产生有害后果。长时间暴露于 糖皮质激素升高对中枢神经系统有不利作用，导致海马 和前额皮质功能障碍、神经和神经内分泌过度反应 对压力的反应。由于过度活跃，澳元的 HPA 反馈受到干扰。有证据表明 防止过度的 HPA 激活将恢复 HPA 负反馈并重置系统 更多的生理水平，减少饮酒和复吸的动机。 虽然压力反应对于生存至关重要，但它可能会失调，从而导致 包括 AUD 在内的多种疾病的发病机制，并可能导致有害的相互作用 澳元和这些条件。该 I 期 SBIR 提出了先导化合物优化和临床前疗效 测试一种新的候选疗法，旨在长期管理病理性 HPA 轴 用于治疗 AUD 的多动症。