权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
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
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/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

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.

项目总结