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