A first-in-class orally bioavailable small molecule dual inhibitor targeting NLRP3 and the dopamine transporter to treat AD

首创的口服生物可利用小分子双重抑制剂，靶向 NLRP3 和多巴胺转运蛋白，用于治疗 AD

• 批准号: 10325722
• 负责人: RUSSELL WAYNE BROWN
• 金额: $ 47万
• 依托单位: P2D, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325722
• 关键词: 3xTg-AD mouse; AD transgenic mice; Address; Adverse effects; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Analysis of Variance; Animal Model; Anxiety; Astrocytes; Automobile Driving; Autopsy; Behavior; Behavioral; Benztropine; Binding; Bioavailable; Biochemical; Biological Assay; Biological Sciences; Brain; Brain region; CASP1 gene; Canis familiaris; Cardiovascular system; Cells; Chronic; Clinical; Cocaine; Cognitive; Data; Decision Making; Dementia; Development; Dialysis procedure; Disease; Disease Progression; Dopamine; Dose; Drug Kinetics; Drug Targeting; Equilibrium; Evaluation; FDA approved; Foundations; Functional disorder; Future; Generations; Hippocampus (Brain); Human; Immune; In Vitro; Incidence; Interleukin-1 beta; Lead; Learning; Leucine-Rich Repeat; Measures; Mediating; Memory; Methods; Microdialysis; Microglia; Modeling; Motivation; Mus; Natural Immunity; Neurocognitive; Neurologic; Neurotransmitters; Nucleotides; Oral; Oral Administration; Outcome Measure; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Plasma; Prevalence; Publishing; Reporting; Research; Rewards; Safety; Small Business Innovation Research Grant; Solid; Stains; Stimulus; Symptoms; TNF gene; Telemetry; Tg2576; Therapeutic; Tissues; Toxicology; Transgenic Animals; Transgenic Model; Transgenic Organisms; United States National Institutes of Health; abeta accumulation; analog; approach behavior; cognitive function; dopamine transporter; drug development; effective therapy; foot; frontal lobe; frontotemporal degeneration; improved; incentive salience; inhibitor/antagonist; interest; marenostrin; mild cognitive impairment; mouse model; neuroinflammation; novel; phase 2 study; pre-clinical; preclinical study; response; small molecule; tau Proteins; therapeutic target; transport inhibitor; uptake

ABSTRACT P2D Bioscience is developing a first-in-class treatment for Alzheimer’s disease (AD). Our drug is an orally-effective combination that targets both innate immunity and the dopamine transport (DAT) inhibitor. Recent studies suggest that TNFα and DAT inhibitors are orally effective treatments for AD in preclinical AD transgenic mouse models. The proposed studies will determine if our compound is an effective treatment for AD using a three transgenic animal models of AD. The rationale is rigorously evaluation for our lead compound across different models of AD pathology in this limited direct-to-phase 2 SBIR application. The proposed specific aims will determine if chronic oral treatment significantly improves AD symptoms and AD /FTD pathophysiology in these animal models. Aim 1 : Determine the brain and plasma PK profile of our dual acting lead compound to aid in developing a PKPD correlation. Aim 2: Determine the efficacy of chronic daily oral treatment of our dual acting lead compound at improving cognitive/behavioral function in three transgenic models of dementia and their AD-associated pathology

摘要 P2 D Bioscience正在开发一种治疗阿尔茨海默病（AD）的一流疗法。我们 药物是一种口服有效的组合，针对先天免疫和多巴胺 转运（DAT）抑制剂。最近的研究表明，TNFα和DAT抑制剂是口服 在临床前AD转基因小鼠模型中有效治疗AD。 拟议的研究将确定我们的化合物是否是一种有效的治疗AD的方法， 三种AD转基因动物模型。理由是严格评估我们的领导 在这一有限的直接进入2期SBIR中， 应用程序.拟议的具体目标将确定慢性口腔治疗是否显著 改善这些动物模型中的AD症状和AD /FTD病理生理学。 目的1：确定我们的双作用先导化合物的脑和血浆PK特征，以帮助 与PKPD的关联性 目的2：确定我们的双作用铅长期每日口服治疗的疗效 化合物在三种痴呆转基因模型中改善认知/行为功能 以及他们的AD相关病理