Novel mGlu5 negative allosteric modulators as first-in-class non-addictive analgesic therapeutics

项目摘要 大量文献提供了令人信服的证据，选择性拮抗剂或负变构调节剂 代谢型谷氨酸（mGlu）受体mGlu 5的NAM具有令人兴奋的潜力，作为一种新的方法， 治疗多种疼痛状况，可提供持续的抗伤害感受活性，而不会出现严重的 与阿片类药物相关的不良反应和滥用责任。虽然许多mGlu 5 NAM已经被推进， 到临床试验，以前的化合物都有严重的缺点，包括药代动力学差， 这些特性和毒性阻碍了它们的进一步发展。因此，这些现有化合物具有 不允许临床研究在患者中严格检验这一假设。我们开发了一个新颖的系列 高选择性的mGlu 5 NAM在结构上与以前的化合物无关，具有优异的性能， 以进一步开发，并避免形成与先前mGlu 5相关的毒性代谢产物 NAMs。基于现有的临床前模型，以及显示mGlu 5 NAM在以下方面的功效的临床试验数据： 对于偏头痛患者，我们预期我们的化合物将在患有偏头痛的患者中具有广谱镇痛活性。 各种慢性疼痛症状。至关重要的是，新的止痛药不受滥用责任的影响， 严重的毒性，这将防止长期管理，这些问题是解决在目前的研究 计划我们已经完成了电极导线优化和体内药代动力学（PK）研究，并确定了多个 临床前候选人。临床前概念验证研究现在将与我们的先导化合物进行测试 mGlu 5 NAM将有效治疗疼痛而无滥用倾向的假设。此外，本发明还 我们将进行正电子发射断层扫描研究，以确定电极导线上的体内受体占有率 候选人这些研究的疗效数据将用于明确确定PK/PD/CNS受体结合率 关系和告知人类剂量预测，并将计划推进到UH 3的活动1阶段 这是一个治愈奖。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）以及可能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）。

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.