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.

项目概要大量文献提供了令人信服的证据，表明选择性拮抗剂或负变构代谢型谷氨酸 (mGlu) 受体 mGlu5 的调节剂 (NAM) 作为一种新型药物具有令人兴奋的潜力用于治疗多种疼痛状况的方法，可以提供持续的抗伤害活性，而无需与阿片类药物相关的严重不良反应和滥用倾向。虽然许多 mGlu5 NAM 具有进入临床试验后，之前的化合物均存在严重缺陷，包括性能较差药代动力学特性和毒性阻碍了它们的进一步发展。因此，这些先行化合物尚未允许临床研究在患者身上严格检验这一假设。我们有开发了一系列新颖的高选择性 mGlu5 NAM，其结构与以前的不相关化合物，具有进一步开发的优异特性，并避免形成有毒代谢物与之前的 mGlu5 NAM 相关。基于现有的临床前模型以及临床试验数据显示 mGlu5 NAM 对偏头痛患者的功效，我们预计我们的化合物将具有对患有各种慢性疼痛的患者具有广谱镇痛活性。至关重要的是新的止痛药不会遭受滥用倾向或严重毒性的影响，从而阻止长期给药，这些问题在当前的研究计划中得到解决。我们建议在体内进行先导化合物优化药代动力学 (PK) 和药效学 (PD) 研究以确定合适的临床前候选药物。将进行临床前概念验证研究，以检验 mGlu5 NAM 将被用于对治疗疼痛有功效。此外，我们将进行正电子发射断层扫描研究确定先导候选物的体内受体占据情况。受体占用数据以及体内 PK 数据，将用于确定在啮齿动物模型中进行功效研究的适当给药方案炎症性疼痛、神经性疼痛和内脏性疼痛。这些研究的功效数据将用于明确建立 PK/PD/CNS 受体占据关系并为人类剂量预测提供信息。确保 mGlu5 NAM 不存在与阿片类药物相关的成瘾特性，将进行自我给药研究评估滥用责任。如果达到 UG3 里程碑，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需要为提交研究新药（IND）申请准备临床前候选药物（PCC）。