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; 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.

项目摘要： 阿尔茨海默氏病与代谢功能障碍，葡萄糖和胰岛素抵抗，氧化应激，氧化应激有关 线粒体功能障碍和降低运动能力。氧化应激和线粒体功能障碍 与β-淀粉样蛋白（Aβ）沉积物的发展相关，这是AD的标志之一。 记忆和认知能力下降的开始。此外，AD患者的寿命降低。根据它 通过增强新陈代谢，葡萄糖和 胰岛素耐受性，运动能力和防止氧化应激，线粒体功能障碍和 凋亡。所有这些特征均存在于5型腺酸环化酶（AC5）敲除（KO）小鼠中， 表现出健康的寿命，与保护AD的所有主要分子因素有关。 Adenylyl cyclese （AC）诱导环状AMP（CAMP），因此调节交感神经控制和β-肾上腺素受体（β- AR）信号传导，因此是从酵母到哺乳动物的生物中健康和寿命的关键调节剂。 AC5是十种AC同工型之一，几乎在体内的每个器官（包括大脑）中表达。 支持其在衰老中的作用，我们发现AC5（AC5 KO）的破坏促进了健康的寿命， 提高运动表现并预防糖尿病和心力衰竭，所有这些都应有帮助 防止阿尔茨海默氏病。我们的初步数据还表明，AC5 KO小鼠在 与野生型小鼠相比，记忆和运动任务。相反，阿尔茨海默氏症型J20小鼠，一种转基因 过表达突变体淀粉样蛋白前体蛋白（APP）的动物表现出记忆力丧失。 AC5的药物抑制剂是临床翻译的目标。我们已经开发了药品 AC5的抑制剂，称为C90，是抑制AC5靶向心肌的主要候选者 缺血。 C90导致强大的AC5抑制作用，具有较高的溶解度，并且容易吸收口服。它显示出效率 在运动和心肌缺血的动物模型中。 C90的主要缺点是存在 羟烷酸基。羟胺与不良反应有关，通常是诱变的。这 羟氨酸酯组的诱变性是由于其重排向异氰酸酯的重排起 DNA的烷基化剂。该应用程序的目的是设计和合成一个保留的新颖C90 C90的生物学活性，但没有羟核酸基的毒性责任。