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: 10581793
• 负责人: P Jeffrey Conn
• 金额: $ 7.66万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581793
• 关键词: Address; Adverse effects; American; Analgesics; Award; Chemistry; Chronic; Clinical Research; Clinical Trials; Contractor; Data; Development; Dose; Drug Kinetics; GRM5 gene; Human; Investigational Drugs; Investigational New Drug Application; Lead; Literature; Metabotropic Glutamate Receptors; Migraine; Opioid; Pain; Pain management; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Positron-Emission Tomography; Pre-Clinical Model; Preparation; Property; Research; Risk; Safety; Series; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; abuse liability; antagonist; base; chronic pain; chronic pain management; chronic pain patient; chronic painful condition; efficacy study; imaging study; in vivo; lead candidate; lead optimization; metabotropic glutamate receptor 5; novel; novel strategies; opioid epidemic; opioid mortality; opioid use; pain model; pain reduction; pre-clinical; prevent; programs; receptor; research clinical testing

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 have completed the lead optimization and in vivo pharmacokinetic (PK) studies and identify multiple preclinical candidates. Preclinical proof of concept studies will now be conducted with our lead compound to test the hypothesis that mGlu5 NAMs will be efficacious in the treatment of pain without abuse liability. Additionally, we will perform positron emission tomography studies to determine in vivo receptor occupancy on the lead candidate. Efficacy data from these studies will be used to clearly establish a PK/PD/CNS receptor occupancy relationship and inform human dose projections and advance the program to the campaign 1 phase of the UH3 phase of this HEALS award. If UG3 milestones are met, a UH3 phase, in partnership with NIH contractors, will include all chemistry, manufacturing and control (CMC) and possibly safety pharmacology and toxicology studies required to prepare a preclinical candidate (PCC) for an investigation new drug (IND) application submission.

项目摘要 大量文献提供了令人信服的证据，表明选择性拮抗剂或负变构调节剂 代谢性谷氨酸(MGlu)受体mGlu5的(NAMS)作为一种新的途径具有兴奋的潜力 治疗多种疼痛状况，可提供持续的抗伤害性活动，而不会出现严重的 与阿片类药物相关的不良影响和滥用责任。虽然已经提出了一些mGlu5NAM 根据临床试验，以前的化合物都存在严重的缺点，包括药代动力学较差。 这些特性和毒性阻碍了它们的进一步发展。因此，这些先前的化合物具有 不允许临床研究在患者身上严格测试这一假设。我们开发了一系列新奇的 在结构上与以前的化合物无关的高选择性mGlu5NAMS具有优异的性能 用于进一步开发，并避免形成与以前的mGlu5相关的有毒代谢物 NAMS。基于现有的临床前模型以及临床试验数据显示mGlu5 NAM在 对于偏头痛患者，我们预计我们的化合物将对患有偏头痛的患者具有广谱镇痛活性。 各种慢性疼痛状况。至关重要的是，新的止痛药不受滥用责任或 严重的毒性会阻止长期服用，这些问题在目前的研究中得到了解决 计划。我们已经完成了先导优化和体内药代动力学(PK)研究，并确定了 临床前候选人。临床前概念验证研究现在将使用我们的先导化合物进行测试 假设mGlu5-NAMS在治疗疼痛方面有效，没有滥用责任。另外， 我们将进行正电子发射断层扫描研究，以确定体内受体在铅上的占有率 候选人。这些研究的疗效数据将被用来清楚地确定PK/PD/CNS受体的占有率 联系和告知人类剂量预测，并将该计划推进到超高浓缩铀活动1阶段3 这一阶段的治愈奖。如果达到了UG3里程碑，UH3阶段将与NIH承包商合作， 包括所有化学、制造和控制(CMC)，并可能包括安全药理学和毒理学研究 需要为研究新药(IND)申请提交准备临床前候选(PCC)。