Tau Protein Aggregation Inhibitors for Tauopathies

描述（由申请人提供）：阿尔茨海默病（AD）的特征是由不溶性β -淀粉样蛋白（A?）组成的脑淀粉样斑块和含有聚集的tau蛋白的神经原纤维缠结（nft）。阿尔茨海默病药物的发现工作主要集中在减少大脑A？层次，更少强调tau定向策略。ProteoTech公司已经开发了许多不同的体外筛选技术和细胞模型，以确定新的有效的淀粉样变性抑制剂。我们设计、合成并测试了一类新的化学实体（NCE），该化学实体由小分子（200-400 MW）组成，其中包含由连接区间隔的多羟基芳香族环。我们的I期SBIR研究结果已经确定了十（10）个先导小分子化合物，它们在体外具有很强的抑制/破坏tau蛋白纤维形成的能力。这一发现已被几位科学家证实

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by brain amyloid plaques consisting of insoluble beta-amyloid protein (A?), and neurofibrillary tangles (NFTs) containing aggregated tau protein. AD drug discovery efforts have been largely focused on reducing brain A? levels, with much less emphasis on tau-directed strategies. ProteoTech Inc. has developed a number of different in vitro screening technologies and cellular models that identified new potent inhibitors of amyloidoses. We have designed, synthesized and tested a class of new chemical entities (NCE) consisting of small molecules (200-400 MW) containing polyhydroxylated aromatic rings spaced by a linker region. Results from our Phase I SBIR studies have identified ten (10) lead small molecule compounds that possess strong potency to inhibit/disrupt tau protein fibril formation in vitro. This discovery has been confirmed by several independent methodologies, including Thioflavin S fluorometry, CD spectroscopy, electron microscopy and cell-based assays. We hypothesize that specific lead polyhydroxylated aromatic compounds can also serve as direct inhibitors of tau aggregation/fibrillogenesis in mouse models of tauopathies. These compounds are believed to possess great potential as new therapeutic agents for AD and related tauopathies. The major objective of our Phase II SBIR project is to identify lead polyhydroxylated aromatic compounds in a relevant mouse model of tauopathy that have the ability to reduce tau-related pathology and to improve tau-induced behavioral deficits. In Specific Aim 1, we will assess the 10 lead small molecule compounds for their drugability, blood-brain-barrier penetration, pharmacokinetic (PK) profiles, and acute toxicity in mice. Three lead small molecule compounds that possess the best brain penetration, peripheral PK, drugability and tolerance in mice will be selected for animal studies in Aim 2. In Specific Aim 2, we will test the three best lead compounds (selected from Aim 1) for their in vivo efficacy in a transgenic mouse model expressing the human P301S mutant tau protein. We will treat mice with three compounds with one of two administration routes (orally or s.c. to be determined from Aim 1 studies) at 3 doses for each compound for 6 months (starting at 3 months of age). The effectiveness of these compounds in reducing tau aggregation/NFT formation, improving tau-related memory deficits, and improving CSF tau biomarker profiles will be determined using staining and quantitative immunohistochemistry, western blotting, ELISAs and behavioral testing including the Morris water maze test. This Phase II SBIR project will lead to a pre-clinical candidate (and back-up) for the treatment of tau aggregation in AD and other tauopathies.