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

摘要 P2D生物科学公司正在开发一种治疗阿尔茨海默病(AD)的一流方法。我们的 药物是一种口服有效的组合，既针对先天免疫，又针对多巴胺。 转运(DAT)抑制剂。最近的研究表明，肿瘤坏死因子α和DAT抑制剂是口服的 临床前AD转基因小鼠模型对AD的有效治疗。 拟议的研究将确定我们的化合物是否有效地治疗AD 三种AD转基因动物模型。理由是对我们的领先地位进行严格的评估 在这一有限的直接到第二阶段SBIR中，跨不同AD病理模型的化合物 申请。拟议的具体目标将决定慢性口服治疗是否显著 改善这些动物模型的AD症状和AD/FTD病理生理学。 目标1：确定我们的双作用铅化合物的脑和血浆PK谱以辅助 在发展PKPD相关性方面。 目的2：确定我们的双效铅慢性每日口服治疗的疗效 复方对三种转基因痴呆模型认知/行为功能的改善作用 以及他们与AD相关的病理

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