Novel Anti-Neuroinflammatory AD Therapeutic

描述(申请人提供)：这项研究的目标是开发一种新的安全有效的疗法，通过靶向激活的胶质细胞和由此产生的神经炎症来改变阿尔茨海默病(AD)的进展。正在测试的假设是，我们的口服生物可用、脑穿透、新型抗神经炎先导化合物在AD相关病理生理学的动物模型中显示有效性，可以进一步开发成一组候选药物，以便最佳临床候选药物可以在建议的研究完成时由确定的行业合作伙伴提交IND文件。我们的新型口服生物利用型、CNS选择性小分子化合物可减少促炎细胞因子IL-1？那肿瘤坏死因子呢？通过激活的胶质细胞，从而产生神经保护和抑制AD相关的病理生理进展。这种发现方法是新颖的，在前端解决了导致晚期药物开发失败的几个根本原因。发现化学使用一种基于片段的方法，其中非活性片段的集中扩展是基于跨学科的Rational分层过程，使用由计算生物学、合成可行性和生物筛选辅助的决策过滤器。从一年前开始，我们将这种方法应用于非活性的3-氨基-6-苯基哒嗪支架的扩展，开发了一套具有合适的分子性质和功能的新型先导化合物。本提案的先导化合物命名为MW01-5-188WH。在AD相关病理生理学的小鼠模型中，在开始控制性脑室注射人A？三周后开始每日口服MW01-5-188WH。抑制与病理生理学相关的海马区IL-1水平升高？和肿瘤坏死因子？，导致改善突触功能障碍，如通过生化终点检测，并改善海马体依赖的行为缺陷。除了口服生物利用度外，MW01-5-188WH还显示出良好的大脑摄取能力，在急性高剂量或慢性治疗剂量下都没有检测到组织毒性。MW01-5-188WH选择性抑制CMS炎症而不是外周炎症。拟议的研究是为了对MW01-5-188WH进行药物化学优化，并对类似物进行生物测试，以保持有效性、选择性、生物利用度、脑摄取和无毒性，同时改善关键的分子特性，如水的溶解度，这些特性与转化研究和后期药物开发的有利结果有关。优化策略利用了导致MW01-5-188WH开发的已建立和验证的平台。这个U01项目有非常可行的年度里程碑，最后一个是由FDA合规的合同研究组织开发与GMP合成兼容的合成方案。

DESCRIPTION (provided by applicant): 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, CNSselective, small molecule compounds reduce the up-regulated production of the pro-inflammatory cytokines IL-1? and TNF? 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 A????? suppresses pathophysiology-associated increases in the hippocampus levels of IL-1? and TNF?, 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.