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、 线粒体功能障碍和运动能力降低。氧化应激与线粒体功能障碍 与β-淀粉样蛋白（A β）沉积的发展相关，A β沉积是AD的标志之一， 记忆力和认知能力的下降此外，AD患者的寿命缩短。因此 将有益于研究具有增强的代谢、葡萄糖和胰岛素的健康长寿的新模型。 胰岛素耐受性、运动能力和抗氧化应激、线粒体功能障碍，以及 凋亡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，与所有主要的分子因素，防止AD。腺苷酸环化酶 (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，因此是从酵母到哺乳动物的生物体中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表达，包括大脑。在 为了支持其在衰老中作用，我们发现AC5的破坏（AC5 KO）促进健康长寿， 增强运动表现，预防糖尿病和心力衰竭，所有这些都应该是有益的 在预防阿尔茨海默病方面。我们的初步数据还表明，AC5 KO小鼠在以下情况下表现更好： 记忆和运动任务相比，野生型小鼠。相比之下，阿尔茨海默病模型J20小鼠，一种转基因小鼠， 过度表达突变型人淀粉样前体蛋白（APP）的动物表现出预期的记忆丧失。 AC5的药理学抑制剂是临床转化的目标。我们开发了一种药理学 AC5的抑制剂，称为C90，作为抑制AC5靶向心肌的主要候选物 缺血C90导致AC5的稳健抑制，具有高溶解度且易于口服吸收。它显示出有效性 在运动和心肌缺血的动物模型中。C90的主要缺点是 异羟肟酸基团。异羟肟酸盐与不良反应有关，通常具有致突变性。的 异羟肟酸基团的致突变性被认为是由于其重排为异氰酸酯， DNA的烷化剂。本申请的目标是设计和合成一种新的C90， 具有C90的生物活性，但没有异羟肟酸基团的毒性倾向。