Brain penetrant Hsp90 inhibitors for Alzheimer's disease

描述(申请人提供)：阿尔茨海默病(AD)的神经变性可能是由于Aβ作为斑块沉积在脑组织中造成的。然而，关于含有tau的神经原纤维缠结(NFTs)在AD中的作用的研究较少。越来越多的证据表明，含有NFTs的tau在AD和其他神经退行性疾病的发生和发展中是一个重要的组成部分。在这项建议中，tau途径是通过抑制分子伴侣热休克蛋白90(Hsp90)作为靶点，作为一种有希望的新途径来影响AD的疾病进展。这项建议建立在STTR第一阶段资助下提出和实现的具体目标的基础上-a)进行结构-活性关系研究，以获得大脑渗透性Hsp90抑制剂，以及b)评估生化和细胞Hsp90抑制。这些努力产生了新颖的、专有的Hsp90抑制剂，具有可接受的药物性质，包括良好的大脑浓度。自第一阶段资助结束以来，Yuma治疗公司已经在小鼠中生成了早期先导化合物YT-17的药代动力学数据，进一步支持了它的类药物特性。拟议的第二阶段研究集中在a)在体内转基因tau病小鼠模型中评估我们的先导化合物对脑脊液中总tau和磷酸化tau的水平、tau神经病理和行为结果的影响；b)扩大候选先导药物的生产规模，并启动体内毒理学研究；c)关于原料药的配方工作。

DESCRIPTION (provided by applicant): Neurodegeneration in Alzheimer's disease (AD) may result from deposition of Aβ as plaques in brain tissue. However, less effort has been made to elucidate the role of tau- containing neurofibrillary tangles (NFTs) in AD. Accumulating evidence suggests that tau containing NFTs is an important component in the initiation and progression of AD and other neurodegenerative diseases. In this proposal the tau pathway is targeted through inhibition of the molecular chaperone heat shock protein 90 (Hsp90) as a promising new approach to affect the disease progression of AD. This proposal builds on the specific aims set forth and achieved under the STTR Phase I funding - a) to conduct structure-activity relationship studies to obtain brain permeable Hsp90 inhibitors and b) to evaluate biochemical and cellular Hsp90 inhibition. These efforts yielded novel, proprietary Hsp90 inhibitors with acceptable drug-like properties including good brain concentration. Since the conclusion of Phase I funding, Yuma Therapeutics has generated pharmacokinetic data in mice for an early lead compound, YT-17, further supporting its drug-like properties. The proposed studies for Phase II focus on a) evaluating our lead compound in an in vivo transgenic mouse model of tauopathy on the levels of total tau and phosphorylated-tau in cerebrospinal fluid, tau neuropathology, and behavioral outcomes; b) manufacturing scale-up of active pharmaceutical ingredient (API) of a lead candidate and initiate in vivo toxicology studies; and c) formulation work on the API.