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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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

抽象的 P2D Bioscience 正在开发一种治疗阿尔茨海默病 (AD) 的一流疗法。该药物是一种口服有效的组合，针对先天免疫和多巴胺最近的研究表明 TNFα 和 DAT 抑制剂是口服的。临床前 AD 转基因小鼠模型中 AD 的有效治疗。拟议的研究将确定我们的化合物是否能有效治疗 AD 三个 AD 转基因动物模型的基本原理是对我们的领先优势进行严格评估。在这个有限的直接进入 2 期 SBIR 中，跨 AD 病理学不同模型的化合物所提出的具体目标将决定慢性口服治疗是否显着。改善这些动物模型中的 AD 症状和 AD /FTD 病理生理学。目标 1：确定我们的双作用先导化合物的大脑和血浆 PK 曲线，以帮助开发 PKPD 相关性。目标 2：确定双效先导药物长期每日口服治疗的疗效改善三种转基因痴呆模型认知/行为功能的化合物及其 AD 相关病理