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，表明选择性拮抗剂或负变构 代谢性谷氨酸(MGlu)受体mGlu5的调节剂(NAM)具有作为一种新的激动剂的潜力 治疗多种疼痛状况的方法，可以提供持续的抗伤害性活动，而不需要 与阿片类药物有关的严重不良影响和滥用责任。而一些mGlu5NAM具有 已经进入临床测试，以前的化合物都存在严重的缺点，包括差 药代动力学特性和毒性阻碍了它们的进一步发展。因此，这些之前的 化合物不允许临床研究在患者身上严格测试这一假设。我们有 开发了一系列新的高度选择性的mGlu5NAMS，在结构上与以前的 化合物，具有良好的进一步开发性能，避免形成有毒代谢物 与先前的mGlu5NAMS相关。基于现有的临床前模型和临床试验 数据显示mGlu5 NAM对偏头痛患者的疗效，我们预计我们的化合物将有 广谱止痛活性在各种慢性疼痛条件下的患者。至关重要的是， 新的止痛药不会受到滥用责任或严重毒性的影响，这些都会阻止长期服用， 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铅优化 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mGlu5NAMS将是 在治疗疼痛方面很有效。此外，我们将进行正电子发射断层扫描研究，以 确定候选铅的体内受体占有率。受体占有率数据，以及体内PK 数据，将被用来确定在啮齿动物模型中进行疗效研究的适当给药方案 炎症性、神经性和内脏疼痛。来自这些研究的疗效数据将被用来明确地确定 PK/PD/CNS受体占位关系，并告知人类剂量预测。确保mGlu5 NAM 没有与阿片类药物有关的成瘾性质，将进行自我给药研究，以 评估滥用责任。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)以及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)。

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.