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

基本信息

批准号：
10405661
负责人：
Vadim Cherezov
金额：
$ 64.76万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
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/10405661
关键词：
AGTR2 gene Absence of pain sensation Affect Afferent Neurons Affinity American Analgesics Angiotensin II Angiotensin Receptor Angiotensins Animals Anxiety Back Pain Binding Biological Assay Brain Bypass Canis familiaris Cells Clinical Coculture Techniques Collaborations Complex Contractor Crystallization Development Diabetes Mellitus Dose Drug Addiction Drug Kinetics Drug usage Economic Burden Epidemic Esthesia Goals Grant Hepatotoxicity Herpes zoster disease Hypersensitivity In Vitro Injections Knockout Mice Lead Ligands MAPK1 gene Measures Mediating Medical 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 Plant Roots 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 Ursidae Family addiction analog antagonist base 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 in vitro Assay in vitro Model in vitro testing in vivo inhibitor lead optimization lead series macrophage 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

项目摘要

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.

项目摘要神经性慢性疼痛影响约2000万美国人，承担超过5000亿美元的负担美国经济。此外，在慢性疼痛中的成瘾性阿片类止痛药的广泛使用是阿片类药物滥用流行病威胁着整个社会。作为四分之一的神经性疼痛患者通过当前治疗方案的体验缓解疼痛，发现治疗神经性的新方法疼痛是未满足的医疗需求，对社会产生了重大影响。靶向周围神经元的疼痛是关键有效和安全镇痛的范式，它们自然可以绕过CNS介导的副作用和瘾。血管紧张素AT2受体是最有前途，最先进的外围靶标之一神经元膜兴奋性和周围感觉神经元神经突生长的法规。抑制 PNS中的AT2R在神经性疼痛的临床前模型以及II期临床试验中显示了影响 ema401药物在疱疹后神经痛患者中表现出镇痛。但是，EMA401，由于离线，这种具有适度的效力和次优的药物样特性已于2019年5月终止高治疗剂量的靶向肝毒性。缺少适合发现的管道中的AT2R候选人以及开发新的高度有效和安全的AT2R拮抗剂，以缓解神经性疼痛。我们已经建立了基于结构的药物发现平台，并用它来识别AT2R拮抗剂的新铅化学型。我们的当前的铅具有与先前临床候选者相当的亲和力（Ki = 56 nm），但配体效率更高，更好的药物样特性和初始SAR提示高优化潜力。而且，最近了解AT2R在神经性疼痛中的神经免疫功能作用方面的突破有助于我们建立一组基于细胞的功能测定，缺乏阻碍了以前的开发工作。使用这些平台，我们计划为我们的主要和备份线索系列建立全面的SAR，并开发一个在该项目的1年UG3阶段进行筛选漏斗。与BPN指导委员会密切合作顾问和承包商，此筛查漏斗将在UH3阶段使用，以优化铅与AT2R铅开发相关的效力，选择性，ADMET和PK特性，包括周围排除CNS副作用的限制。这将允许选择临床开发候选者以预先开发，辅助研究和靶向颅后神经痛的IND的准备。