权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of a Novel Anti-Neuroinflammatory AD Therapeutic

新型抗神经炎症 AD 治疗药物的开发

基本信息

批准号：
7544825
负责人：
Daniel Martin Watterson
金额：
$ 7.55万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/7544825
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Acute Address Alzheimer&apos 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-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 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

项目摘要

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.

这项研究的目标是开发一种新的安全有效的治疗方法来改变阿尔茨海默氏症