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: 10645104
• 负责人: Vadim Cherezov
• 金额: $ 60.74万
• 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/10645104
• 关键词: AGTR2 gene; Absence of pain sensation; Affect; Afferent Neurons; Affinity; American; Analgesics; Angiotensin Receptor; Angiotensins; Animals; Anxiety; Back Pain; Binding; Biological Assay; Brain; Bypass; Canis familiaris; Cells; Clinical; Coculture Techniques; Collaborations; Complex; Contractor; Development; Diabetes Mellitus; Dose; Drug Addiction; Drug Kinetics; Drug usage; Economic Burden; Epidemic; Esthesia; Genetic; Goals; Grant; Hepatotoxicity; Herpes zoster disease; Hypersensitivity; In Vitro; Injections; Knockout Mice; Lead; Ligands; Macrophage; Measures; Mediating; Medical; Medicine; Membrane; Mental Depression; Modeling; Motivation; Mus; Nerve Fibers; Neuralgia; Neurites; Neuroimmune; Neuroimmunomodulation; Neurons; Nociceptors; Opiate Addiction; Opioid; Opioid Analgesics; Oral; Output; Pain; Pain management; Patients; Penetration; Peripheral; Peripheral Nerves; Peripheral Nervous System; Persons; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Postherpetic neuralgia; Postoperative Pain; Pre-Clinical Model; Preparation; Production; Property; Receptor Inhibition; Receptor Signaling; Regulation; Resolution; Risk; Rodent; Role; Safety; Signal Transduction; Societies; Structural Biologist; Structure; Structure-Activity Relationship; Synthesis Chemistry; System; Testing; Therapeutic; Toxicology; Type 2 Angiotensin II Receptor; addiction; analog; antagonist; behavior test; behavioral response; cardiovascular effects; cellular targeting; chemical synthesis; chemotherapy; chronic neuropathic pain; chronic pain; chronic pain relief; clinical candidate; clinical development; drug discovery; drug seeking behavior; experience; improved; in vitro Assay; in vitro Model; in vitro testing; in vivo; inhibitor; lead optimization; lead series; mouse model; multidisciplinary; non-opioid analgesic; novel; novel strategies; opioid abuse; opioid epidemic; opioid overdose; pain relief; painful neuropathy; pre-clinical; preclinical development; prescription opioid; receptor; response; scaffold; scale up; screening; side effect; therapeutic target

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.

项目摘要 神经病理性慢性疼痛影响~2000万美国人，给美国带来超过5000亿美元的负担 美国经济。此外，成瘾性阿片类止痛药的广泛使用是慢性疼痛的主要根源。 阿片类药物滥用流行威胁着整个社会。因为只有四分之一的神经病理性疼痛患者 体验当前治疗选项的疼痛缓解，发现治疗神经性疾病的新方法 疼痛是一种未得到满足的医疗需求，对社会有重大影响。针对外周神经元的疼痛是一个关键 有效和安全的镇痛范例，可以自然地绕过中枢神经系统介导的副作用和 上瘾。血管紧张素AT2受体是最有希望和最先进的外周靶点之一，它参与了 神经元膜兴奋性与周围感觉神经元突起生长的调节。抑制 AT2R在PNS中已经在神经病理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， EMA401药物在带状疱疹后神经痛患者中显示出止痛作用。然而，EMA401， 效力适中，类药物性能不佳，已于2019年5月终止，原因是 高治疗性剂量的靶向肝毒性。缺乏合适的AT2R候选人需要发现 以及开发治疗神经病理性疼痛的高效、安全的新型AT2R拮抗剂。我们已经建立了一个 基于结构的药物发现平台，并使用它来识别AT2R拮抗剂的新的先导化学类型。我们的 目前的铅具有与先前临床候选药物相同的亲和力(Ki=56 nM)，但配基效率要高得多， 更好的类药物特性和初步的SAR表明有很高的优化潜力。此外，最近 在了解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 建立一套基于细胞的功能分析，这一点阻碍了以前的开发工作。vbl.使用 在这些平台上，我们计划为我们的主要和备用领导系列建立全面的SAR，并开发 该项目为期一年的UG3阶段的筛选漏斗。在BPN指导委员会的密切合作下， 顾问和承包商，然后将在UH3阶段使用此筛选漏斗来优化销售线索 与AT2R铅开发相关的效力、选择性、ADMET和PK属性，包括外围设备 排除中枢神经系统副作用的限制。这将使临床开发候选人的选择成为可能 针对带状疱疹后神经痛的IND的开发、使能研究和制备。