A Novel Pharmacological Inhibitor of Adenylyl Cyclase Type 5 to Treat Alzheimer's Disease

项目总结： 阿尔茨海默病与代谢障碍、葡萄糖和胰岛素抵抗、氧化应激、 线粒体功能障碍，运动能力下降。氧化应激与线粒体功能障碍 与β-淀粉样蛋白(A-β)沉积的发展有关，这是早在几年前就开始的AD的特征之一 记忆力和认知能力衰退的开始。此外，阿尔茨海默病患者的寿命会缩短。因此，它 将有益于研究新的健康长寿模型，通过增强新陈代谢、葡萄糖和 胰岛素耐量、运动能力和对氧化应激、线粒体功能障碍的保护，以及 细胞凋亡。所有这些特征都存在于腺酰环化酶5(AC5)基因敲除(KO)小鼠中，该小鼠 表现出健康的长寿，与所有预防AD的主要分子因素有关。腺酰环化酶 (Ac)诱导环磷酸腺苷(CAMP)，从而调节交感神经控制和β肾上腺素能受体(β- AR)信号，因此在从酵母到哺乳动物的各种生物中，它是健康和长寿的关键调节因子。 AC5是十种AC亚型之一，几乎在身体的每个器官中都有表达，包括大脑。在……里面 支持其在衰老中的作用，我们发现AC5(AC5 KO)的破坏促进了健康长寿， 提高运动能力，预防糖尿病和心力衰竭，所有这些都应该是有帮助的 在预防阿尔茨海默病方面。我们的初步数据还显示，AC5 KO小鼠在 与野生型小鼠的记忆和运动任务进行比较。相比之下，阿尔茨海默病模型J20小鼠，一种转基因 过度表达突变的人类淀粉样前体蛋白(APP)的动物，如预期的那样表现出记忆丧失。 AC5的药理抑制剂是临床翻译的目标。我们已经开发出一种药理 AC5的抑制剂，被称为C90，是AC5靶向心肌抑制的主要候选者 缺血症。C90对AC5有很强的抑制作用，具有很高的溶解度，很容易被口服吸收。它显示了它的有效性 在运动和心肌缺血的动物模型中。C90的主要缺点是存在 异羟肟酸组。羟色胺类药物与不良反应有关，而且往往具有诱变性。这个 异丙酮酸根的致突变性是由于其重排为异氰酸酯所致。 DNA的烷基化试剂。这项申请的目标是设计和合成一种新型的C90，它将保留 C90的生物活性，但不具有异羟肟酸基的毒性。

Project Summary: Alzheimer’s Disease is associated with metabolic dysfunction, glucose and insulin resistance, oxidative stress, mitochondrial dysfunction, and reduced exercise capacity. Oxidative stress and mitochondrial dysfunction correlate with the development of beta-amyloid (Aβ) deposits, one of the hallmarks of AD that begin years before the onset of memory and cognitive decline. Moreover, patients with AD have a reduced lifespan. Accordingly, it would be beneficial to examine novel models of healthful longevity with enhanced metabolism, glucose and insulin tolerance, exercise capacity, and protection against oxidative stress, mitochondrial dysfunction, and apoptosis. All these features are present in the adenylyl cyclase type 5 (AC5) knock out (KO) mouse, which exhibits healthful longevity, associated with all major molecular factors that protect against AD. Adenylyl cyclase (AC) induces cyclic AMP (cAMP) and, therefore, regulates sympathetic control and β-adrenergic receptor (β- AR) signaling, and is thus a key regulator of health and longevity in organisms ranging from yeast to mammals. AC5 is one of ten AC isoforms and is expressed in virtually every organ in the body, including the brain. In support of its role in aging, we have found that disruption of AC5 (AC5 KO) promotes healthful longevity, enhances exercise performance and protects against diabetes and heart failure, all of which should be helpful in protecting against Alzheimer’s Disease. Our preliminary data also show that AC5 KO mice perform better on memory and motor tasks compared to wild-type mice. In contrast, the Alzheimer model J20 mice, a transgenic animal that overexpresses mutant human amyloid precursor protein (APP), exhibits memory loss as expected. A pharmacological inhibitor of AC5 is the goal for clinical translation. We have developed a pharmacological inhibitor of AC5, which is known as C90, as the lead candidate for the inhibition of AC5 targeting myocardial ischemia. C90 leads to robust inhibition of AC5, has high solubility and readily absorbed orally. It showed efficacy in animal models of exercise and myocardial ischemia. The main drawback with C90 is the presence of a hydroxamic acid group. Hydroxamates are associated with adverse effects and are often mutagenic. The mutagenicity of the hydroxamate group is proposed be due to its rearrangement to isocyanate which act as alkylating agents of DNA. The goal of this application is to design and synthesize a novel C90 that would retain the biological activity of C90, but devoid of the toxic liability of a hydroxamic acid group.