Development of neutral sphingomyelinase 2 (nSMase2) inhibitors for the treatment of Alzheimer's disease

开发用于治疗阿尔茨海默病的中性鞘磷脂酶 2 (nSMase2) 抑制剂

• 批准号: 10777029
• 负责人: Rana Rais
• 金额: $ 65.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10777029
• 关键词: ABCB1 gene; Address; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Area; Autopsy; Biochemical; Biogenesis; Biological Assay; Brain; Canis familiaris; Carbamates; Ceramides; Cognition; Cognitive deficits; Contralateral; Development; Disease Outcome; Dose; Drug Kinetics; Encapsulated; Enzymes; Excretory function; Exhibits; Generations; Genes; Genetic; Goals; Hippocampus; Human; Hydrolysis; Impaired cognition; In Vitro; Liver; Medical; Membrane; Metabolism; Modeling; Modification; Molecular; Monitor; Mus; Neurology; Oral; Pathogenicity; Pathologic; Pathologic Processes; Permeability; Pharmaceutical Preparations; Phosphorylcholine; Physiological Processes; Plasma; Play; Pyridazines; Rattus; Reporting; Research Personnel; Role; Series; Skeleton; Solubility; Sphingomyelinase; Sphingomyelins; Structure-Activity Relationship; Study Section; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Mice; Weight; absorption; analog; aqueous; clinical translation; dentate gyrus; drug discovery; efficacy evaluation; efficacy study; efficacy testing; extracellular vesicles; glial activation; human old age (65+); improved; in vivo; inhibitor; intercellular communication; mouse model; multidisciplinary; mutant; nanomolar; neuron loss; nonhuman primate; novel; object recognition; pharmacologic; pre-clinical; preclinical study; prevent; prototype; scaffold; small molecule; tau Proteins; tau aggregation; transgenic model of alzheimer disease; translational potential; vesicular release

PROJECT SUMMARY Neutral sphingomyelinase 2 (nSMase2 encoded by SMPD3 gene) is a membrane associated enzyme that catalyzes the hydrolysis of sphingomyelin (SM) into phosphorylcholine and ceramide. Formation of ceramide- enriched areas by the action of nSMase2 is known to facilitate generation of extracellular vesicles, which participate in intercellular communication in both physiological and pathological processes through encapsulation and transfer of diverse types of substances including tau protein. Interestingly, post-mortem brains from AD patients exhibit abnormal increases in ceramide. Inhibition of nSMase2 has therefore become an attractive therapeutic strategy to treat AD by inhibiting EV biogenesis to slow the spread of pathogenic cargo. The main objective of this project is to conduct structural optimization using (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6- dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate (PDDC), a prototype nSMase2 inhibitor, as a molecular template with the ultimate goal of identifying development candidates with balanced overall pharmacological profiles required for clinical translation. By assembling a multidisciplinary team of investigators with complementary expertise, we are poised to seize this opportunity by executing the following specific aims; (Aim 1) Conduct structure-activity relationship (SAR) studies on nSMase2 inhibitors containing a core scaffold different from that of PDDC; (Aim 2) Characterize the ADME (absorption, distribution, metabolism and excretion) and in vitro selectivity/toxicity profile of potent nSMase2 inhibitors from Aim 1. Identify optimal dosing for efficacy studies in Aim 3; (Aim 3) Evaluate selected nSMase2 inhibitors from Aim 2 for efficacy and tolerability in an AAV tau propagation model and a PS19 transgenic model of AD.

项目总结 中性鞘磷脂酶2(NSMase2)由SMPD3基因编码，是一种膜相关酶。 催化神经鞘磷脂(SM)的水解为磷酰胆碱和神经酰胺。神经酰胺的形成- 已知由nSMase2作用的富集区有助于细胞外小泡的产生，这 通过参与生理和病理过程中的细胞间通讯 不同类型物质的包裹和转移，包括tau蛋白。有趣的是，死后的大脑 来自AD患者的神经酰胺异常增加。因此，抑制nSMase2已成为一种 有吸引力的治疗策略，通过抑制EV的生物发生来减缓病原货物的传播来治疗AD。 本项目的主要目标是利用(R)-(1-(3-(3，4-二甲氧基苯基)-2，6- Dimethylimidazo[1，2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate(Pdc)，nSMase2抑制剂的原型 分子模板，最终目标是确定总体平衡的开发候选 临床翻译所需的药理学资料。通过组建一个多学科的调查小组 凭借互补的专业知识，我们准备通过执行以下具体目标来抓住这一机会； (目标1)含核心支架的nSMase2抑制剂的构效关系(SAR)研究 不同于PDDC；(目标2)表征ADME(吸收、分布、代谢和排泄) 和来自AIM的有效的nSMase2抑制剂的体外选择性/毒性分布1.确定最佳剂量的疗效 目标3中的研究；(目标3)评估从目标2中选择的nSMase2抑制剂在AAV中的有效性和耐受性 Tau繁殖模型和pS19转基因AD模型。