Novel mGlu5 Negative Allosteric Modulators as First-in-Class Non-Addictive Analgesic Therapeutics

新型 mGlu5 负变构调节剂作为一流的非成瘾性镇痛治疗药物

基本信息

批准号：
10477066
负责人：
P Jeffrey Conn
金额：
$ 19.12万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477066
关键词：
Absence of pain sensation Address Adverse effects Aldehyde oxidase American Analgesics Anemia Back Canis familiaris Capsaicin Cardiovascular Physiology Chemicals Chemistry Chronic Clinic Clinical Research Clinical Trials Clinical Trials Network Contractor Contracts Cutaneous Data Development Dose Drug Kinetics Ensure Exhibits GRM5 gene Human Investigational Drugs Investigational New Drug Application Lead Literature Lung Macaca fascicularis Metabolic Pathway Metabolism Metabotropic Glutamate Receptors Migraine Modeling Molecular Opioid Pain Pain management Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacology and Toxicology Phase Placebos Plasma Positron-Emission Tomography Pre-Clinical Model Preparation Primates Property Rapid screening Rattus Regimen Research Risk Rodent Rodent Model Safety Self Administration Series Testing Therapeutic Time Toxic effect Toxicology United States National Institutes of Health Validation Visceral pain abuse liability analytical method antagonist appropriate dose base chronic pain chronic pain management chronic pain patient chronic painful condition clinical development clinical pain drug metabolism efficacy study experimental study fenobam human subject improved in vivo inflammatory pain inter-individual variation lead candidate lead optimization metabotropic glutamate receptor 5 method development non-opioid analgesic novel novel strategies opioid epidemic opioid mortality opioid use pain model pain reduction painful neuropathy pharmacokinetics and pharmacodynamics pre-clinical prevent receptor research clinical testing scaffold screening therapeutic candidate translational study

项目摘要

Project Summary An extensive literature provides compelling evidence that selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have exciting potential as a novel approach for treatment of multiple pain conditions that could provide sustained antinociceptive activity without the serious adverse effects and abuse liability associated with opioids. While a number of mGlu5 NAMs have been advanced to clinical testing, the previous compounds all suffer from serious shortcomings, including poor pharmacokinetic properties and toxicity that have prevented their further development. Therefore, these prior compounds have not allowed for clinical studies to rigorously test this hypothesis in patients. We have developed a novel series of highly selective mGlu5 NAMs that are structurally unrelated to previous compounds, have excellent properties for further development, and avoid the formation of toxic metabolites that were associated with previous mGlu5 NAMs. Based on existing preclinical models, as well as clinical trial data showing efficacy of an mGlu5 NAM in migraine patients, we anticipate that our compounds will have broad-spectrum analgesic activity in patients with a variety of chronic pain conditions. It will be essential that new pain drugs do not suffer from abuse liability or severe toxicity that would prevent chronic administration, and these issues are addressed in the current research plan. We propose to conduct lead optimization, in vivo pharmacokinetic (PK), and pharmacodynamic (PD) studies to identify suitable preclinical candidates. Preclinical proof of concept studies will be conducted to test the hypothesis that mGlu5 NAMs will be efficacious in the treatment of pain. Additionally, we will perform positron emission tomography studies to determine in vivo receptor occupancy on lead candidates. Receptor occupancy data, along with in vivo PK data, will be used to determine the appropriate dosing regimen for efficacy studies in rodent models of inflammatory, neuropathic, and visceral pain. Efficacy data from these studies will be used to clearly establish a PK/PD/CNS receptor occupancy relationship and inform human dose projections. To ensure mGlu5 NAMs are void of the addictive qualities associated with opioid drugs, self-administration studies will be conducted to evaluate abuse liability. If UG3 milestones are met, a UH3 phase, in partnership with NIH contractors, will include all chemistry, manufacturing and control (CMC) and safety pharmacology and toxicology studies required to prepare a preclinical candidate (PCC) for an investigation new drug (IND) application submission.

项目摘要广泛的文献提供了令人信服的证据，表明选择性拮抗剂或负变构成代谢型谷氨酸（MGLU）受体MGLU5的调节剂（NAM）具有令人兴奋的潜力治疗多种疼痛状况的方法，可以提供持续的抗伤害感受活性与阿片类药物相关的严重不利影响和虐待责任。虽然许多MGLU5 NAM有先前的化合物都遭受了严重的缺点，其中包括差的差，包括较差药代动力学特性和毒性阻止了它们的进一步发展。因此，这些先验化合物不允许临床研究严格检验患者的假设。我们有开发了一系列新型高度选择性的MGLU5 NAM，这些NAM与以前的结构无关化合物具有出色的进一步发展特性，并避免形成有毒代谢物与以前的MGLU5 NAM有关。基于现有的临床前模型以及临床试验数据显示MGLU5 NAM在偏头痛患者中的功效，我们预计我们的化合物将具有各种慢性疼痛疾病患者的广谱镇痛活性。至关重要新的疼痛药物不会遭受虐待责任或严重毒性，这会阻止长期给药，这些问题在当前的研究计划中解决了。我们建议进行铅优化，体内药代动力学（PK）和药效学（PD）研究，以鉴定合适的临床前候选者。将进行临床前概念研究证明，以检验MGLU5 NAM的假设有效治疗疼痛。此外，我们将进行正电子发射断层扫描研究确定铅候选者的体内受体占用率。受体占用数据，体内PK 数据将用于确定在啮齿动物模型中的疗效研究的适当给药方案炎症，神经性和内脏疼痛。这些研究的疗效数据将用于清楚建立 PK/PD/CNS受体占用关系并为人类剂量预测提供信息。确保mglu5 nams 没有与阿片类药物相关的成瘾品质，将进行自我管理研究评估虐待责任。如果达到UG3里程碑，则与NIH承包商合作的UH3阶段将包括所有化学，制造和控制（CMC）以及安全药理学和毒理学研究为调查新药（IND）提交准备临床前候选者（PCC）所需。