Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics

项目摘要 本申请，“Discovery of PSD 95 protein-protein interaction inhibitors as novel non-opioid analgesics”， 解决了对治疗慢性神经性疼痛的更有效药物的迫切需要。疼痛是 与医疗保健系统的接触比任何其他单一原因都多，但治疗选择 神经性疼痛的疗效有限，并且具有包括阿片成瘾在内的副作用的高风险。这些 这些因素每年为已经紧张的美国医疗保健系统增加560 - 6350亿美元。 谷氨酸激活N-甲基-D-天冬氨酸（NMDA）受体介导中枢神经系统（CNS） 致敏，其涉及神经性疼痛的发展和维持。NMDA介导的 中枢致敏依赖于在受体处形成多蛋白级联复合物， NMDA受体与支架蛋白、突触后密度蛋白95（PSD 95）结合， 神经元型一氧化氮合酶（nNOS）。通过将这些蛋白质紧密结合在一起， 被激活，导致神经网络重组（可塑性）和神经元细胞死亡。小分子和 破坏这种复合物的细胞穿透肽在临床前动物模型中作为有效的镇痛剂， 副作用优于非选择性NMDA受体拮抗剂和NOS抑制剂。我们的团队， 发表了一种靶向这种复合物的小分子，IC 87201，证明了其在临床前疼痛模型中的疗效。 类似的小分子，ZL 006，在临床前中风模型中是有效的。我们设计并合成了一种独特的 以及一组新的IC 87201和ZL 006类似物，将一个分子推进IND使能研究，用于后 创伤应激障碍在确定了候选分子的问题后，我们系统地重新设计了 它产生了一组新的分子。在推进之前，需要进一步的资金来改进这些分子。 新的IND研究。重要的是，候选分子的先进毒理学研究 表明靶向特异性副作用风险低，并预测具有 可接受的活性和药物样性质。在SBIR第I/II阶段快速通道应用中，Anagin与 我们的合作者和蓝图神经治疗网络，将设计和测试分子，以改善药物， 类似的性质，在体外和离体测定中证实靶点接合，证明在临床前疼痛中的功效 使用行为模型建立治疗边界。我们会推荐一个新的临床候选人 分子通过IND使能研究。不符合我们设定标准的化合物将不会被推进。在 这些研究的结论，我们将有一个新的临床候选人彻底审问，并准备 用于慢性疼痛的临床试验。本提案中总结的数据有力地表明，我们的方法 将产生有效的镇痛剂，其治疗指数优于开发或临床中的其它化合物。 这些化合物可能在许多其他谷氨酸驱动的CNS疾病中有用。

Project Summary This application, “Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics”, addresses the critical need for more effective medications to treat chronic neuropathic pain. Pain is responsible for more encounters with the health care system than any other single cause, yet treatment options for neuropathic pain have limited efficacy and carry a high risk for side effects, including opioid addiction. These factors add an additional $560-635 billion annually to an already strained United States health care system. Glutamate activation of N-methyl-D-aspartate (NMDA) receptors mediates central nervous system (CNS) sensitization, which is implicated in the development and maintenance of neuropathic pain. NMDA-mediated central sensitization depends on formation of a multi-protein cascade complex at the receptor consisting of the NMDA receptor bound to the scaffolding protein, postsynaptic density protein 95 (PSD95), and recruitment of neuronal nitric oxide synthase (nNOS). By bringing these proteins close together, multiple signaling cascades are activated leading to neural network reorganization (plasticity) and neuronal cell death. Small molecules and cell penetrating peptides that disrupt this complex act as effective analgesics in preclinical animal models with better side effect profiles than non-selective NMDA receptor antagonists and NOS inhibitors. Our team, the first to publish a small molecule targeting this complex, IC87201, demonstrated its efficacy in preclinical pain models. A similar small molecule, ZL006, is effective in preclinical stroke models. We designed and synthesized a unique and novel set of IC87201 and ZL006 analogs, advancing one molecule into IND-enabling studies for post- traumatic stress disorder. After identifying concerns with the candidate molecule, we systematically redesigned it resulting in a new set of molecules. Further funding is needed to improve on these molecules prior to advancing them toward new IND-enabling studies. Importantly, advanced toxicology studies with the candidate molecule suggest a low risk of target specific side effects and predict an excellent therapeutic index for compounds with acceptable activity and drug-like properties. In this SBIR Phase I/II fast track application, Anagin, in concert with our collaborators and the Blueprint Neurotherapeutics Network, will design and test molecules for improved drug- like properties, confirm target engagement in in vitro and ex vivo assays, demonstrate efficacy in preclinical pain models and establish a therapeutic margin using behavioral models. We will advance a new clinical candidate molecule through IND-enabling studies. Compounds that do not meet our set criteria will not be advanced. At the conclusion of these studies, we will have a new clinical candidate thoroughly interrogated and poised for testing in clinical trials for chronic pain. Data summarized in this proposal strongly suggests that our approach will yield effective analgesics with better therapeutic indices than other compounds in development or the clinic. These compounds are likely to be useful in many other glutamate-driven CNS diseases.