A Novel Insulin Pathway Agonist for Alzheimer's Disease

描述（由申请人提供）：尽管-淀粉样蛋白肽(A)沉积与阿尔茨海默病（AD）的关联支持了疾病进展和可能的病因的主要假设，并且一些解决-淀粉样蛋白斑块形成或去除的药物已经进入临床试验，但迄今为止还没有有效的治疗AD的药物。这一现实需要新的靶点，这些靶点不是基于淀粉样蛋白供应侧或去除，而是针对其对关键神经元存活、代谢和可塑性途径的毒性作用。越来越多的人认识到，AD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，既能恢复胰岛素敏感性，又能加速a¿的去除。我们发现了一种未命名的PDK-1激酶变乙酰激活剂（CAS 1180676-32-7或PS48）的文献优先权，这是一种氯苯戊酸。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其他类似作用化合物的支架。就这样几个小图书馆

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.