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

一种治疗阿尔茨海默病的新型 5 型腺苷酸环化酶药理抑制剂

• 批准号: 10608477
• 负责人: STEPHEN F VATNER
• 金额: $ 25.21万
• 依托单位: VASADE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10608477
• 关键词: Adenylate Cyclase; Adverse effects; Affinity; Age; Age Months; Aging; Alkylating Agents; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Apoptosis; Applications Grants; Biological; Biological Assay; Brain; Cerebrospinal Fluid; Chronic Disease; Cyclic AMP; DNA; Data; Dementia; Deposition; Development; Diabetes Mellitus; Drug Kinetics; Exercise; Exhibits; FDA approved; Glucose; Goals; Half-Life; Health; Heart failure; Human Amyloid Precursor Protein; Hydroxamic Acids; Impaired cognition; In Vitro; Insulin Resistance; Isocyanates; J20 mouse; Knock-out; Knockout Mice; Longevity; Mammals; Memory; Memory Loss; Metabolic dysfunction; Metabolism; Modeling; Molecular; Motor; Mus; Myocardial Ischemia; Obesity; Oral; Organ; Organism; Oxidative Stress; Performance; Pharmaceutical Preparations; Plasma; Population; Prevalence; Property; Protein Isoforms; Research; Rodent; Role; Senile Plaques; Signal Transduction; Solubility; Testing; Transgenic Animals; Wild Type Mouse; Yeasts; absorption; adenylyl cyclase type V; aging population; analog; behavioral phenotyping; beta-adrenergic receptor; clinical candidate; clinical translation; design; exercise capacity; glucose tolerance; hydroxamate; improved; in vivo; inhibitor; insulin tolerance; lead candidate; mitochondrial dysfunction; mutant; new therapeutic target; novel; overexpression; pharmacologic; response; virtual; virtual library

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.

项目概要： 阿尔茨海默病与代谢功能障碍、葡萄糖和胰岛素抵抗、氧化应激、 线粒体功能障碍，以及氧化应激和线粒体功能障碍。 与 β-淀粉样蛋白 (Aβ) 沉积物的形成相关，这是多年前开始的 AD 的标志之一 此外，AD 患者的寿命也会相应缩短。 将有利于研究通过增强新陈代谢、葡萄糖和 胰岛素耐受性、运动能力以及针对氧化应激、线粒体功能障碍的保护，以及 所有这些特征都存在于腺苷酸环化酶 5 型 (AC5) 敲除 (KO) 小鼠中。 表现出健康长寿，与预防 AD 的所有主要分子因素有关。 (AC) 诱导环磷酸腺苷 (cAMP)，因此调节交感神经控制和 β-肾上腺素能受体 (β- AR）信号传导，因此是从酵母到哺乳动物等生物体健康和长寿的关键调节因子。 AC5 是十种 AC 异构体​​之一，几乎在身体的每个器官中表达，包括大脑。 支持其在衰老中的作用，我们发现 AC5 的破坏（AC5 KO）可以促进健康长寿， 增强运动表现并预防糖尿病和心力衰竭，所有这些都应该有所帮助 我们的初步数据还表明，AC5 KO 小鼠在预防阿尔茨海默病方面表现更好。 与野生型小鼠相比，阿尔茨海默病模型 J20 小鼠的记忆和运动任务。 过度表达突变型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的药理学抑制剂是临床转化的目标，我们已经开发出一种药理学抑制剂。 AC5 抑制剂，称为 C90，是抑制 AC5 靶向心肌的主要候选药物 C90对AC5有很强的抑制作用，溶解度高，口服容易吸收。 在运动和心肌缺血的动物模型中，C90 的主要问题是存在 异羟肟酸基团具有不良反应并且通常具有致突变性。 异羟肟酸酯基团的致突变性被认为是由于其重排为异氰酸酯，异氰酸酯的作用是 该应用的目标是设计和合成一种能够保留 DNA 的新型 C90。 C90 的生物活性，但没有异羟肟酸基团的毒性。