A Novel Insulin Pathway Agonist for Alzheimer's Disease

描述(申请人提供)：尽管淀粉样蛋白(A)沉积与阿尔茨海默病(AD)之间的联系是疾病进展和可能原因的主要假说的基础，几种解决淀粉样斑块形成或移除的药物已经进入临床试验，但到目前为止还没有有效的治疗AD的方法。这一现实需要新的靶点，而不是基于淀粉样蛋白的供应面或移除，而是解决其对关键神经元存活、代谢和可塑性途径的毒性影响。人们越来越多地认识到，阿尔茨海默病是一种影响大脑的胰岛素抵抗状态，即所谓的“II型糖尿病”。在我们的研究中，我们发现了一种潜在的新疗法，既可以恢复胰岛素敏感性，又可以加速A？的清除。我们发现了一种未命名的变构激活剂，即一种氯苯基戊烯酸，它是一种未命名的变构激活剂，即pdk-1(CAS 1180676-32-7或PS48)。当在培养细胞和无细胞系统中进行测试时，发现PS48通过恢复Akt的激活来逆转负淀粉样蛋白效应。我们建议利用它的结构和活性作为发现更多类似作用化合物的支架。通过这种方式，有几个小图书馆 将基于PS48进行制备和测试，以尝试和优化该先导化合物的治疗效果和其他药理性质。

DESCRIPTION (provided by applicant): Even though the association of ¿-amyloid peptide (A¿) deposition and Alzheimer's Disease (AD) underpins the major hypothesis for disease progression and possibly causation and several drugs addressing the formation or removal of ¿-amyloid plaques have entered clinical trials, no effective therapy exists to date for AD. This reality calls for new targets that are not based on ¿-amyloid supply side or removal but address its toxic effects on critical neuronal survival, metabolic and plasticity pathways. There is widening recognition that AD is an insulin resistant state affecting the brain, a so-called 'type II diabetes' In our studies, we have found a potential novel therapy to both restore insulin sensitivity and hasten A¿ removal. We found literature precedence for an unnamed allosteric activator of the kinase PDK-1 (CAS 1180676-32-7 or PS48), a chlorophenyl pentenoic acid. When tested in cultured cells and cell-free systems, PS48 was found to be reverse the negative amyloid effect by restoring Akt activation. We propose to use its structure and activity as a scaffold for the discovery of additional like-acting compounds. In this way several small libraries based on PS48 will be prepared and tested to try and optimize the therapeutic effect and other pharmacologic properties of this lead compound.