Development of a Novel Anti-Neuroinflammatory AD Therapeutic

这项研究的目标是开发一种新的安全有效的治疗方法，改变阿尔茨海默氏症 通过靶向激活的神经胶质和由此产生的神经炎症来控制疾病（AD）的进展。的假设 正在测试的是，我们的口服生物利用度，脑渗透，新的抗神经炎症的铅化合物， 在AD相关病理生理学的动物模型中显示功效的药物可以进一步开发成一组 候选药物，使得最佳临床候选药物可以由确定的工业生产商提交IND申请。 完成拟议的调查。我们的新型口服生物可利用的CNS- 选择性的小分子化合物减少促炎细胞因子的上调产生 IL-1 β和TNF α通过活化的胶质细胞，从而产生神经保护和AD相关的抑制。 病理生理学进展发现方法是新颖的，并在前端解决了以下几个问题： 药物开发后期失败的根本原因。发现化学使用基于碎片的 一种基于合理的层次结构对非活性片段进行集中扩展的方法， 过程是跨学科的，采用决策过滤器辅助计算生物学，合成 可行性和生物筛选。从一年前开始，我们将这种方法应用于 无活性的3-氨基-6-苯基哒嗪支架，并开发了一组新的先导化合物， 适当的分子性质和功能。本提案的先导化合物称为MW 01 -5- 188WH。在AD相关病理生理学的小鼠模型中，每日经口给予MW 01 -5- 188 WH 在开始控制性脑室内输注人Af ^42抑制剂后三周开始， 海马IL-1 β和TNF α水平的病理生理学相关增加，导致 通过生物化学终点测定的突触功能障碍的改善，以及 依赖于大脑的行为缺陷除了口服生物有效性之外，MW 01 -5- 188 WH还显示 在急性高剂量或慢性治疗剂量下，脑摄取良好，且无可检测的组织毒性。 MW 01 -5- 188 WH选择性抑制CMS炎症而不是外周炎症。拟议 研究是为了优化MW 01 -5- 188 WH的药物化学和类似物的生物学测试， 保留疗效、选择性、生物利用度、脑摄取和无毒性，同时改善关键 分子特性，如水溶性，已与有利的结果， 转化研究和后期药物开发。优化策略利用已建立的 并验证了导致MW 01 -5- 188 WH开发的平台。U 01项目具有很高的可行性， 年度里程碑，最后一个是开发与GMP兼容的合成方案 由FDA合规合同研究组织进行合成。

The goal of this research is to develop a new class of safe and effective therapeutics that alter Alzheimer's disease (AD) progression by targeting activated glia and the resultant neuroinflammation. The hypothesis being tested is that our orally bioavailable, brain-penetrant, novel anti-neuroinflammatory lead compound that shows efficacy in animal models of AD-relevant pathophysiology can be developed further into a set of drug candidates such that a best clinical candidate can be taken to an IND filing by an identified industrial partner at the completion of the proposed investigations. Our novel class of orally bioavailable, CNS- selective, small molecule compounds reduce the up-regulated production of the pro-inflammatory cytokines IL-1(3 and TNFa by activated glia, with a resultant neuroprotection and suppression of AD-relevant pathophysiology progression. The discovery approach is novel and addresses at the front end several of the root causes for late stage drug development failure. The discovery chemistry uses a fragment-based approach in which a focused expansion of an inactive fragment is done based on a rational hierarchal process that is interdisciplinary, employing decision filters assisted by computational biology, synthetic feasibility, and biological screens. Starting one year ago, we applied this approach to the expansion of the inactive 3-amino-6-phenylpyridazine scaffold and developed a novel set of lead compounds with the appropriate molecular properties and function. The lead compound for this proposal is termed MW01-5- 188WH. In a mouse model of AD-relevant pathophysiology, daily oral administration of MW01-5-188WH begun three weeks after the start of controlled intracerebroventricular infusion of human Af^.42 suppresses pathophysiology-associated increases in the hippocampus levels of IL-1p and TNFa, resulting in the improvement of synaptic dysfunction, as assayed by biochemical endpoints, and improvement in hippocampal-dependent behavioral deficits. In addition to being orally biovailable, MW01-5-188WH shows good brain uptake and no detectable tissue toxicity at either acute high doses or chronic therapeutic doses. MW01-5-188WH selectively suppresses CMS inflammation versus peripheral inflammation. The proposed studies are for medicinal chemistry optimization of MW01-5-188WH and biological testing of the analogs for retention of efficacy, selectivity, bioavailability, brain uptake and lack of toxicity while improving key molecular properties, such as aqueous solubility, that have been linked to favorable outcomes in translational research and late stage drug development. The optimization strategy utilizes the established and validated platform that led to the development of MW01-5-188WH. This U01 project has highly feasible annual milestones, with the final one being development of a synthetic protocol compatible with GMP synthesis by an FDA compliant contract research organization.