Non-addictive Angiotensin AT2 inhibitors for neuropathic pain relief

项目摘要 神经性慢性疼痛影响约2000万美国人，并承担超过5000亿美元的负担。 美国经济。此外，成瘾性阿片类止痛药对慢性疼痛的广泛使用是慢性疼痛的主要根源。 阿片类药物滥用流行病威胁着整个社会。只有四分之一的神经性疼痛患者 体验疼痛缓解与目前的治疗方案，发现新的方法来治疗神经病变 疼痛是一种未得到满足的医疗需求，对社会有重大影响。靶向外周神经元的疼痛是关键 有效和安全镇痛的范例，它可以自然地绕过CNS介导的副作用， 成瘾血管紧张素AT2受体是最有前途和最先进的外周靶点之一，参与了 调节神经元膜兴奋性和外周感觉神经元突起生长。抑制 PNS中的AT2R已经在神经性疼痛的临床前模型中以及在II期临床试验中显示出效果， 其中EMA 401药物在患有疱疹后神经痛的患者中显示出镇痛作用。然而，EMA401， 其具有适度的效力和次优的药物样性质，已于2019年5月终止，原因是 以高治疗剂量靶向肝毒性。管道中缺乏合适的AT2R候选者需要发现 和开发新的高效和安全的AT2R拮抗剂用于神经病理性疼痛。我们建立了 基于结构的药物发现平台，并使用它来鉴定AT2R拮抗剂的新的先导化学型。我们 目前的先导化合物具有与先前的临床候选物相当的亲和力（Ki =56 nM），但配体效率高得多， 更好的药物样性质和初始SAR表明高优化潜力。此外，最近 在理解AT2R在神经病理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，缺乏这阻碍了以前的发展努力。使用 这些平台，我们计划为我们的主要和备用铅系列建立全面的SAR，并开发一个 筛选漏斗在1年UG3阶段的项目。在与业务方案网指导委员会的密切合作下， 咨询顾问和承包商，然后在UH3阶段采用该筛选漏斗，以优化潜在客户 与AT2R电极导线开发相关的效价、选择性、ADMET和PK特性，包括外周 排除CNS副作用的限制。这将允许选择临床开发候选药物进行预试验， 开发、IND使能研究和制备针对疱疹后神经痛的IND。

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.