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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要中性鞘磷脂酶 2（由 SMPD3 基因编码的 nSMase2）是一种膜相关酶，催化鞘磷脂 (SM) 水解成磷酰胆碱和神经酰胺。神经酰胺的形成- 已知通过 nSMase2 作用形成的富集区域可促进细胞外囊泡的生成，参与生理和病理过程中的细胞间通讯包括 tau 蛋白在内的多种物质的封装和转移。有趣的是，死后大脑 AD 患者的神经酰胺异常增加。因此，抑制 nSMase2 已成为一种通过抑制 EV 生物发生以减缓致病物质的传播来治疗 AD 是一种有吸引力的治疗策略。该项目的主要目标是利用(R)-(1-(3-(3,4-二甲氧基苯基)-2,6- 二甲基咪唑并[1,2-b]哒嗪-8-基)吡咯烷-3-基)-氨基甲酸酯 (PDDC)，一种原型 nSMase2 抑制剂，作为分子模板，最终目标是确定总体平衡的发展候选者临床转化所需的药理学特征。通过组建多学科研究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）对含有核心支架的 nSMase2 抑制剂进行构效关系 (SAR) 研究与PDDC不同；（目标 2）表征 ADME（吸收、分布、代谢和排泄）以及来自目标 1 的有效 nSMase2 抑制剂的体外选择性/毒性特征。确定功效的最佳剂量研究目标 3；（目标 3）评估目标 2 中选定的 nSMase2 抑制剂在 AAV 中的功效和耐受性 tau 繁殖模型和 AD 的 PS19 转基因模型。