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
基本信息
- 批准号:10608477
- 负责人:
- 金额:$ 25.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Adenylate CyclaseAdverse effectsAffinityAgeAge MonthsAgingAlkylating AgentsAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmyloid beta-ProteinAnimal ModelApoptosisApplications GrantsBiologicalBiological AssayBrainCerebrospinal FluidChronic DiseaseCyclic AMPDNADataDementiaDepositionDevelopmentDiabetes MellitusDrug KineticsExerciseExhibitsFDA approvedGlucoseGoalsHalf-LifeHealthHeart failureHuman Amyloid Precursor ProteinHydroxamic AcidsImpaired cognitionIn VitroInsulin ResistanceIsocyanatesJ20 mouseKnock-outKnockout MiceLongevityMammalsMemoryMemory LossMetabolic dysfunctionMetabolismModelingMolecularMotorMusMyocardial IschemiaObesityOralOrganOrganismOxidative StressPerformancePharmaceutical PreparationsPlasmaPopulationPrevalencePropertyProtein IsoformsResearchRodentRoleSenile PlaquesSignal TransductionSolubilityTestingTransgenic AnimalsWild Type MouseYeastsabsorptionadenylyl cyclase type Vaging populationanalogbehavioral phenotypingbeta-adrenergic receptorclinical candidateclinical translationdesignexercise capacityglucose tolerancehydroxamateimprovedin vivoinhibitorinsulin tolerancelead candidatemitochondrial dysfunctionmutantnew therapeutic targetnoveloverexpressionpharmacologicresponsevirtualvirtual library
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('STEPHEN F VATNER', 18)}}的其他基金
Skeletal Muscle and Brown Adipose Mechanisms Mediating Cardiovascular Risk Factor Protection in RGS14 KO
RGS14 KO 中骨骼肌和棕色脂肪机制介导心血管危险因素保护
- 批准号:
9900047 - 财政年份:2017
- 资助金额:
$ 25.21万 - 项目类别:
Angiogenesis Protection Induced by sFRP3 Myocyte/Vascular Cross-Talk
sFRP3 肌细胞/血管交互作用诱导的血管生成保护
- 批准号:
9900045 - 财政年份:2017
- 资助金额:
$ 25.21万 - 项目类别:
RGS 14 Disruption, Vascular Effects Leading to Cardioprotection
RGS 14 破坏、血管效应导致心脏保护
- 批准号:
8888575 - 财政年份:2015
- 资助金额:
$ 25.21万 - 项目类别:
RGS 14 Disruption, Vascular Effects Leading to Cardioprotection
RGS 14 破坏、血管效应导致心脏保护
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9102537 - 财政年份:2015
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$ 25.21万 - 项目类别:
Skeletal Muscle Basis for Improved Exercise Endurance in RGS14 KO
RGS14 KO 中提高运动耐力的骨骼肌基础
- 批准号:
9513046 - 财政年份:2011
- 资助金额:
$ 25.21万 - 项目类别:
Skeletal Muscle Basis for Improved Exercise Endurance in AC5 KO
AC5 KO 中提高运动耐力的骨骼肌基础
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8193326 - 财政年份:2011
- 资助金额:
$ 25.21万 - 项目类别:
Skeletal Muscle Basis for Improved Exercise Endurance in AC5 KO
AC5 KO 中提高运动耐力的骨骼肌基础
- 批准号:
8497469 - 财政年份:2011
- 资助金额:
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