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镇痛疗法

• 批准号: 10450295
• 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
• 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/10450295
• 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; Structure; Testing; Therapeutic; Time; Toxic effect; Toxicology; United States National Institutes of Health; Validation; Visceral pain; analytical method; appropriate dose; base; chronic pain; 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

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 大量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剂 代谢型谷氨酸（mGlu）受体mGlu 5的调节剂（NAM）作为一种新型药物具有令人兴奋的潜力 治疗多种疼痛状况的方法，其可提供持续的抗伤害感受活性， 与阿片类药物相关的严重不良反应和滥用风险。虽然许多mGlu 5 NAM具有 虽然已经进入临床试验，但以前的化合物都存在严重的缺点，包括不良反应。 药物代谢动力学特性和毒性已经阻止了它们的进一步发展。因此，这些先前 这些化合物还不允许临床研究在患者中严格地检验该假设。我们有 开发了一系列新的高选择性mGlu 5 NAM，这些NAM在结构上与以前的NAM无关。 化合物，具有进一步开发的优异性能，并避免形成有毒代谢物 与既往mGlu 5 NAM相关。基于现有的临床前模型以及临床试验 显示mGlu 5 NAM在偏头痛患者中的功效的数据，我们预期我们的化合物将具有 在患有各种慢性疼痛病症的患者中具有广谱镇痛活性。至关重要的是， 新的止痛药不具有滥用倾向或严重毒性（这将妨碍长期给药）， 这些问题在目前的研究计划中得到了解决。我们建议在体内进行电极导线优化 药代动力学（PK）和药效学（PD）研究以鉴定合适的临床前候选物。 将进行临床前概念验证研究，以检验mGlu 5 NAM 治疗疼痛有效。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有率。受体结合率数据，沿着体内PK 数据，将用于确定啮齿动物模型中有效性研究的适当给药方案， 炎症性、神经性和内脏疼痛。这些研究的疗效数据将用于明确确定 PK/PD/CNS受体占有关系并为人体剂量预测提供信息。确保mGlu 5 NAM 缺乏与阿片类药物相关的成瘾性，将进行自我给药研究， 评估滥用责任。如果UG 3里程碑得到满足，与NIH承包商合作的UH 3阶段将 包括所有化学、生产和控制（CMC）以及安全药理学和毒理学研究 需要为新药研究（IND）申请提交准备临床前候选药物（PCC）。