Small molecule therapeutics for Alzheimer's Disease

小分子药物治疗阿尔茨海默病 总结： 阿尔茨海默病（AD）是一种进行性和致命的神经系统疾病，影响大约一个- 占65岁以上人口的十分之一。目前没有治愈这种疾病的方法。病理 这种疾病的特征包括β-淀粉样蛋白（AAPs）在脑中的形成和积累，广泛存在于脑中。 被认为是AD的主要神经毒性剂和治疗靶点。塞纳有一种新技术 其不靶向β-或γ-分泌酶，这已经产生了肽药物候选物P8和P4， 在体外和在AD的Tg小鼠模型中抑制A β产生的能力。P4和P8给出了 与人APP 695的纯化胞外域的强、特异性和生物学相关结合。P8是在预- 在其作为治疗AD的候选药物的开发中处于临床阶段。这将是一个明显的优势 为了鉴定可以通过与肽相同的机制减少Ablation的小分子化合物， APP与P4和P8位于相同的站点。这些小分子候选物可被开发为口服药物， 可以通过BBB。在第一阶段资助期间，我们进行了分子建模研究，以预测 APP上P4和P8的结合位点。完成后，我们实际上筛选了一个电子图书馆- 化合物来鉴定那些被预测与APP上与P4和P8相同的位点结合的分子。 在筛选的~ 160，000个结构中，总共有249个结构表明在P4或P8结合处与APP结合。 绝佳的价钱其中，我们能够成功地发现几个候选人，可以减少40和42 在AD患者来源的诱导多能干细胞（ipsc）测定中降低50-80%。在第二阶段的应用中，我们 建议开发最好的三种化合物，A1，A2和A3，进一步作为可能的口服可用的疾病- 修饰用于治疗AD的小分子药物候选物，其以与治疗AD相同的机制起作用。 我们的候选肽 我们的具体目标是：1）进行早期ADME和药代动力学的合成和评价 (PK)2）设计和合成化合物A1-A3的新类似物， 在基于AD ipsc细胞的测定中评价它们的早期ADME和PK性质以及它们降低ADME的能力， 3)研究所选化合物在阿尔茨海默氏症转基因小鼠模型中的药理学/功效 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.