Non-addictive Angiotensin AT2 inhibitors for neuropathic pain relief

用于缓解神经性疼痛的非成瘾性血管紧张素 AT2 抑制剂

• 批准号: 10396694
• 负责人: Vadim Cherezov
• 金额: $ 68.5万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396694
• 关键词: Non; addictive; Angiotensin; AT2; inhibitors

Project Summary Neuropathic chronic pain affects ~20 million of Americans and bears more than US$500 Billion burden on the US economy. Moreover, the widespread use of addictive opioid painkillers for chronic pain is the major root of the opioid abuse epidemics threatening the whole society. As only one in four patients with neuropathic pain experiences pain relief with the current treatment options, discovery of new approaches to treating neuropathic pain is an unmet medical need with a major impact on society. Targeting pain in peripheral neurons is a key paradigm for effective and safe analgesia, which can naturally bypass the CNS-mediated side effects and addiction. One of the most promising and advanced peripheral targets, angiotensin AT2 receptor is involved in regulations of neuronal membrane excitability and neurite outgrowth of peripheral sensory neurons. Inhibition of AT2R in PNS has shown effect in preclinical models of neuropathic pain, as well as in phase II clinical trials, where the EMA401 drug demonstrated analgesia in patients with post-herpetic neuralgia. However, EMA401, which had modest potency and suboptimal drug-like properties, has been terminated in May 2019 due to off- target hepatotoxicity at high therapeutic doses. Lack of suitable AT2R candidates in pipeline calls for discovery and development of new highly potent and safe AT2R antagonists for neuropathic pain. We have established a structure-based drug discovery platform and used it to identify new lead chemotypes for AT2R antagonists. Our current lead has affinity (Ki =56 nM) on par with the previous clinical candidate, but much higher ligand efficiency, better drug-like properties and initial SAR suggesting high optimization potential. Moreover, recent breakthroughs in understanding the neuroimmune functional role of AT2R in neuropathic pain helped us to establish a set of cell-based functional assays, lack of which hampered previous development efforts. Using these platforms, we plan to establish comprehensive SAR for our main and backup lead series, and develop a screening funnel in the 1-year UG3 phase of the project. In close collaboration with the BPN steering committee, consultants and contractors, this screening funnel will then be employed in UH3 phase to optimize the lead potency, selectivity, ADMET and PK properties relevant for AT2R lead development, including peripheral restriction that precludes CNS side effects. This would allow selection of clinical development candidate for pre- development, IND-enabling studies and preparation of IND targeting post-herpetic neuralgia.

项目概要 神经性慢性疼痛影响约 2000 万美国人，并给人类带来超过 5000 亿美元的负担 美国经济。此外，广泛使用成瘾性阿片类止痛药来治疗慢性疼痛是导致慢性疼痛的主要原因。 阿片类药物滥用流行病威胁着整个社会。只有四分之一的患者患有神经性疼痛 通过当前的治疗方案体验疼痛缓解，发现治疗神经病的新方法 疼痛是一种未得到满足的医疗需求，对社会产生重大影响。针对周围神经元的疼痛是关键 有效和安全镇痛的范例，可以自然地绕过中枢神经系统介导的副作用 瘾。血管紧张素 AT2 受体是最有前途和最先进的外周靶标之一，参与 神经元膜兴奋性和周围感觉神经元神经突生长的调节。抑制 PNS 中的 AT2R 在神经性疼痛的临床前模型以及 II 期临床试验中显示出效果， 其中 EMA401 药物对带状疱疹后神经痛患者具有镇痛作用。然而，EMA401， 该药物的效力有限且类药特性欠佳，已于 2019 年 5 月终止，原因是 - 在高治疗剂量下针对肝毒性。管道中缺乏合适的 AT2R 候选药物需要发现 并开发新的高效且安全的 AT2R 拮抗剂来治疗神经性疼痛。我们已经建立了一个 基于结构的药物发现平台，并用它来识别 AT2R 拮抗剂的新先导化学型。我们的 当前先导化合物的亲和力 (Ki = 56 nM) 与之前的临床候选药物相当，但配体效率更高， 更好的药物样特性和初始 SAR 表明具有较高的优化潜力。而且，最近 在理解 AT2R 在神经性疼痛中的神经免疫功能作用方面的突破帮助我们 建立了一套基于细胞的功能测定方法，缺乏这些方法阻碍了之前的开发工作。使用 在这些平台上，我们计划为我们的主要和备用先导系列建立全面的SAR，并开发一个 项目 1 年 UG3 阶段的筛选漏斗。与 BPN 指导委员会密切合作， 顾问和承包商，该筛选漏斗将在 UH3 阶段使用，以优化领先优势 与 AT2R 先导药物开发相关的效力、选择性、ADMET 和 PK 特性，包括外设 排除中枢神经系统副作用的限制。这将允许选择临床开发候选者 针对带状疱疹后神经痛的 IND 开发、IND 启用研究和准备。