IND- and NDA-enabling toxicology studies for PTI-125, a novel small molecule for Alzheimer's disease

 描述(申请人提供)：PTI-125是一种具有新靶点的新型化合物，旨在治疗和减缓阿尔茨海默病(AD)的进展。PTI-125通过与细丝蛋白A(Flna)上的特定位点非常紧密地结合来发挥作用，我们最近证明了一种蛋白质对β淀粉样蛋白的毒性至关重要。β-淀粉样蛋白1-42(A42)通过结合和劫持A7-烟碱型乙酰胆碱受体(A7nAChR)发挥其毒性作用，扰乱其正常功能，并导致AD患者大脑中发现的标志性缠结和斑块。我们最近发现，A？42的这种有毒信号需要FLNA的帮助，当A？42与7nAChR结合时，FLNA被招募来与7nAChR相互作用。通过7nAChR传递的S中毒信号也会损害另外两种对认知、记忆和神经元存活至关重要的受体的功能，即NMDA型受体和胰岛素受体。通过破坏Fla-a7nAChR的结合，PTI-125可阻止A？42‘-S的毒性效应，并恢复这三种受体的正常功能。PTI-125还破坏了FLNA与Toll样受体-4(TLR-4)的类似联系，TLR-4是一种负责释放炎性细胞因子的受体；因此，PTI-125还有第二个功能，即阻断AD脑中的炎症。PTI-125已分别通过Ames和Herg测试(非GLP)的致突变性和心脏毒性。它很容易通过血脑屏障，估计有75%的口服生物利用度，对于候选药物来说有合理的半衰期。在小鼠体内口服两个月是安全的。我们从脑片培养实验中得知其在脑组织中的有效浓度。PTI-125准备开始拟议的IND使能研究，以确保在临床试验之前的安全性。在该提案中，我们的第一阶段工作将包括非GLP剂量选择研究、更正式的PK/ADME工作、遗传毒性研究以及先前开发的分析和生物分析方法的GLP验证。除非在接近预期治疗剂量的剂量范围内出现意外毒性，否则我们将进入第二阶段的工作范围：GLP安全药理学和支持首个人类研究和临床试验的4周和慢性GLP毒理学研究。 在AD和NDA中。

 DESCRIPTION (provided by applicant): PTI-125 is a novel compound with a novel target, designed to treat and slow the progression of Alzheimer's disease (AD). PTI-125 works by binding extremely tightly to a particular site on filamin A (FLNA), a protein we recently demonstrated to be critical to beta amyloid's toxicity. Beta amyloid1-42 (Aß42) exerts its toxic effects by binding and hijacking the a7-nicotinic acetylcholine receptor (a7nAChR), disrupting its normal function and causing the signature tangles and plaques found in brains of AD patients. We recently showed that this toxic signaling by Aß42 requires the help of FLNA, which is recruited to interact with a7nAChR when Aß42 binds this receptor. Aß42's toxic signaling via a7nAChR also impairs the function of two other receptors key to cognition, memory and neuronal survival, the NMDA receptor and the insulin receptor. By disrupting the FLNA - a7nAChR association, PTI-125 prevents Aß42's toxic effects and restores normal function of these three receptors. PTI-125 also disrupts a similar association of FLNA with toll-like receptor-4 (TLR-4), a receptor responsible for releasing inflammatory cytokines; hence, PTI-125 has a second function of blocking the inflammation noted in AD brain. PTI-125 has passed the Ames and hERG tests (non-GLP) for mutagenicity and cardiac toxicity, respectively. It easily passes the blood brain barrier, has an estimated 75% oral bioavailability and has a reasonable half-life for a drug candidate. It was safe given orally for two months in mice. We know the effective concentrations in brain from brain slice culture experiments. PTI- 125 is ready to start the proposed IND-enabling studies to ensure safety prior to a clinical trial. In this proposal, our Phase I work will include the non-GLP dose selection studies, more formal PK/ADME work, genotoxicity studies and the GLP validation of previously developed analytical and bioanalytical methods. Barring unexpected toxicity in a dose range close to the anticipated therapeutic dose, we will proceed to the Phase II scope of work: GLP safety pharmacology and both 4-week and chronic GLP toxicology studies that would support a first-in-human study as well as clinical trials in AD and an NDA.