Development of a Novel Anti-Neuroinflammatory AD Therapeutic

新型抗神经炎症 AD 治疗药物的开发

• 批准号: 7446688
• 负责人: Daniel Martin Watterson
• 金额: $ 44.94万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446688
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Acute; Address; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Appendix; Area; Attenuated; Behavioral; Bioavailable; Biochemical; Biological; Biological Assay; Biological Availability; Biological Testing; Biological feedback; Biology; Biotechnology; Blood; Blood - brain barrier anatomy; Brain; Budgets; Cardiac; Cells; Chemicals; Chemistry; Chronic; Class; Clinical; Clinical Trials; Compatible; Computational Biology; Consultations; Contracts; Cultured Cells; Cytokine Suppression; Daily; Data; Development; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug toxicity; Elderly; End Point; Experimental Designs; Failure; Feasibility Studies; Foundations; Functional disorder; Funding; Goals; Guanosine Monophosphate; Hippocampus (Brain); Histology; Human; In Vitro; Inflammation; Inflammatory; Infusion procedures; Injury; Interleukin-1; Interleukin-10; Investigation; Kidney; Lead; Letters; Licensing; Link; Liver; Liver Microsomes; Lung; Measurement; Mental disorders; Metabolic; Metabolism; Modeling; Molecular; Mus; Neuroglia; Numbers; Oral; Oral Administration; Outcome; Outsourcing; PTGS2 gene; Paper; Patient Noncompliance; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenothiazines; Plague; Plant Roots; Population; Positioning Attribute; Principal Investigator; Probability; Process; Production; Property; Protocols documentation; Published Comment; Pyridazines; Research; Research Contracts; Research Personnel; Safety; Sampling; Scientist; Screening procedure; Series; Solubility; Staging; Standards of Weights and Measures; Structure; Structure-Activity Relationship; Synapses; Synthesis Chemistry; TNF gene; Technology Transfer; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Translational Research; Treatment Protocols; United States Food and Drug Administration; Universities; Week; Work; analog; aqueous; base; cost; cost effective; cyclooxygenase 2; cytokine; depressive symptoms; design; desire; drug development; drug discovery; follow-up; human NOS2A protein; improved; in vivo; innovation; mouse model; neglect; neuroinflammation; neuroprotection; novel; older patient; phenothiazine; pre-clinical; pyridazine; response; scaffold; scale up; small molecule; success; uptake

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.

描述（由申请人提供）：本研究的目标是开发一类新的安全有效的疗法，通过针对激活的神经胶质细胞和由此产生的神经炎症来改变阿尔茨海默氏病（AD）的进展。正在测试的假设是，我们的口服生物利用度、脑渗透性、新型抗神经炎症先导化合物在 AD 相关病理生理学动物模型中显示出功效，可以进一步开发为一组候选药物，以便在完成拟议的研究后，由确定的工业合作伙伴将最佳临床候选药物提交 IND 备案。我们新型口服生物可利用的中枢神经系统选择性小分子化合物可减少促炎细胞因子 IL-1 的上调产生？和肿瘤坏死因子？通过激活的神经胶质细胞，从而产生神经保护并抑制 AD 相关的病理生理学进展。该发现方法是新颖的，并在前端解决了后期药物开发失败的几个根本原因。发现化学采用基于片段的方法，其中基于跨学科的合理分层过程，采用计算生物学、合成可行性和生物筛选辅助的决策过滤器，对非活性片段进行集中扩展。从一年前开始，我们应用这种方法来扩展无活性的 3-氨基-6-苯基哒嗪支架，并开发了一组具有适当分子特性和功能的新型先导化合物。该提案的先导化合物被称为 MW01-5-188WH。在 AD 相关病理生理学的小鼠模型中，在开始控制性脑室内输注人 A 的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 IL-1 水平增加？和 TNF?，导致突触功能障碍的改善（通过生化终点检测）以及海马依赖性行为缺陷的改善。除了具有口服生物利用度外，MW01-5-188WH 在急性高剂量或慢性治疗剂量下均表现出良好的脑吸收性并且没有可检测到的组织毒性。 MW01-5-188WH 选择性抑制 CMS 炎症与外周炎症。拟议的研究旨在对 MW01-5-188WH 进行药物化学优化，并对类似物进行生物测试，以保留功效、选择性、生物利用度、脑吸收和无毒性，同时改善关键分子特性，例如水溶性，这些特性与转化研究和后期药物开发的良好结果相关。该优化策略利用了已建立并经过验证的平台，该平台导致了 MW01-5-188WH 的开发。该 U01 项目具有高度可行的年度里程碑，最后一个里程碑是由符合 FDA 要求的合同研究组织开发与 GMP 合成兼容的合成方案。