Small molecule therapeutics for Alzheimer's Disease

阿尔茨海默病的小分子治疗 摘要： 阿尔茨海默病(AD)是一种进行性和致命性的神经疾病，大约有一种- 65岁以上人口的十分之一。目前还没有治愈这种疾病的方法。病态的 该病的特征包括在大脑中形成和积聚广泛的β-淀粉样蛋白(A？) 被公认为阿尔茨海默病的主要神经毒性药物和治疗靶点。塞纳有一项新技术 这并不针对ç-或γ-分泌酶，后者产生了候选多肽药物P8和P4 在体外和在阿尔茨海默病的TG小鼠模型中抑制Aü的产生的能力。P4和P8给出一个 与纯化的人APP695胞外结构域具有强的、特异性的和生物相关的结合。P8在Pre- 作为治疗阿尔茨海默病的候选药物开发的临床阶段。这将是一个明显的优势 鉴定小分子化合物，这些小分子化合物可以通过与多肽结合的相同机制来还原A？ APP与P4和P8位于同一站点。这些小分子候选药物可能被开发为口服药物 可以穿过血脑屏障。在第一阶段资助期间，我们进行了分子建模研究，以预测 P4和P8在APP上的结合位点。完成后，我们实际上筛选了一个电子图书馆- 化合物来识别那些被预测与P4和P8结合在APP上相同位置的分子。 在筛选的约160,000个结构中，总共有249个结构建议在P4或P8结合时与APP结合 地点。其中，我们成功地发现了几个可以同时减少A？40和42的候选者 在AD患者来源的诱导多能干细胞(IPSC)试验中减少了50%-80%。在此第2阶段应用程序中，我们 建议进一步开发最佳的A1、A2和A3三种化合物。 修饰治疗AD的小分子候选药物，其作用机制与 我们的候选多肽。 我们的具体目标是：1)开展ADME的早期合成和药代动力学研究 (Pk)化合物A1-A3，2)设计和合成化合物A1-A3的新类似物 评估它们的早期ADME和PK特性，以及它们在AD iPSC细胞检测中降低A？的能力 3)研究所选化合物在阿尔茨海默病转基因小鼠模型中的药理/疗效 疾病。

SMALL MOLECULE THERAPEUTICS FOR ALZHEIMER'S DISEASE SUMMARY: Alzheimer's disease (AD) is a progressive and fatal neurological disorder that affects approximately one- tenth of the population over the age of 65. There is currently no cure for the disease. The pathological hallmarks of the disease include the formation and accumulation in the brain of ß-amyloid (Aß), widely recognized to be the major neurotoxic agent in AD and therapeutic target. Cenna has a novel technology that does not target the ß- or γ-secretases, which has yielded peptide drug candidates P8 and P4 with the ability to inhibit the production of Aß in vitro and in a Tg mouse model of AD. P4 and P8 give a strong, specific and biologically relevant binding with the purified ectodomain of human APP 695. P8 is at pre- clinical stage in its developemnt as a drug candidates for the treatment of AD. It would be a distinct advantage to identify small molecule compounds that can reduce Aß by the same mechanism as the peptides, by binding APP at the same sites as P4 and P8. These small molecule candidates may be developed as oral drugs that can cross the BBB. During the Phase 1 funding period we carried out molecular modeling studies to predict binding sites on APP for both P4 and P8. Having accomplished that, we virtually screened a library of e- compounds to identify those molecules that would be predicted to bind the same sites on APP as P4 and P8. Of the ~160,000 structures screened, a total of 249 suggested binding to APP at either the P4 or P8 binding site. Of those, we were able to successfully discover several candidates that could reduce both Aß 40 and 42 by 50-80% in an AD patient-derived induced pluripotent stem cell (ipsc) assay. In this Phase 2 application we propose to develop the best three compounds, A1, A2 and A3 further as possible orally-available disease- modifying small molecule drug candidates for the treatment of AD, that function with the same mechanism as our peptide candidates. Our Specific Aims are 1) to carry out the synthesis and evaluation in early ADME and Pharmacokinetic (PK) properties of compounds A1-A3, 2) to design and synthesize novel analogs of compounds A1-A3 and to evaluate their early ADME and PK properties and their ability to reduce Aß in the AD ipsc cell-based assay and 3) to study the pharmacology/efficacy of selected compounds in a transgenic mouse model of Alzheimer's disease.