A Novel-designed sulfonylurea compound for Vascular Dementia Therapy

一种用于血管性痴呆治疗的新型磺酰脲类化合物

基本信息

批准号：
10726896
负责人：
Jiukuan Hao
金额：
$ 43.99万
依托单位：
UNIVERSITY OF HOUSTON
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：
2023-06-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726896
关键词：
Address Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Anti-Inflammatory Agents Antiinflammatory Effect Area Bilateral Binding Blood Blood - brain barrier anatomy Blood brain barrier dysfunction Brain Brain Diseases Brain Injuries CASP1 gene Carotid Stenosis Cell Culture Techniques Cells Cerebral Ischemia Cerebrovascular Disorders Chemicals Chronic Cognitive Common carotid artery Complex Data Dementia Development Endothelial Cells Excision Foundations Future Goals Homeostasis Hypertension Immune In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Investigation Ischemia Lead Link Lipopolysaccharides Macrophage Mediating Metabolic Microglia Modeling Movement Mus NOS2A gene Neurodegenerative Disorders Neuroimmune Neurons Nucleotides Nutrient Outcome Pathogenesis Pathologic Pathway interactions Phagocytosis Play Poison Regulation Research Rest Role Series Sulfonylurea Compounds TNF gene Therapeutic Therapeutic Effect Tight Junctions Toxic effect Toxin Vascular Cognitive Impairment Vascular Dementia Vascular Endothelial Cell brain endothelial cell cell type cerebral hemodynamics cerebral hypoperfusion cognitive function cytokine design drug development drug discovery effective therapy hypoperfusion improved improved outcome in vivo innovation migration mouse model nervous system disorder neuron loss novel novel therapeutic intervention pharmacologic pharmacophore rational design receptor recruit scaffold small molecule success systemic inflammatory response translational potential uptake vascular inflammation

项目摘要

Summary Inflammation plays important roles in the progression of vascular dementia, and targeting inflammation will give a great promise for slowing the progression of vascular dementia and improving cognitive functions. The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in regulation of endothelial cell and microglia-induced inflammation. Elevated NLRP3 expression in microglia has been implicated in pathogenesis of vascular dementia. Inhibition of microglia-and brain endothelial cell-mediated inflammation by targeting aberrant NLRP3 activation has emerged as a novel, promising therapeutic approach for treatment of vascular dementia and other neurodegenerative disorders. Our preliminary data show that AMS-17, a novel molecule modified from sulfonylurea compound, has anti-inflammatory effect against LPS-induced inflammation in microglia by inhibiting activities of the NLRP3. Furthermore, AMS-17 improves cognitive functions and protects neurons from death in mouse vascular dementia model. This proposal is proposed to investigate therapeutic effects and elucidate its mechanism of action using vascular dementia model in mouse. Our goal is to develop a lead molecule for NLRP3 inhibition with high selectivity, adequate metabolic stability, and low toxicity that can be used to improve cognitive outcomes of vascular dementia. If success, the lead molecule will give a new effective treatment approach for vascular dementia and other neurodegenerative diseases. The overall impact of the project is highly significant in advancing drug discovery for brain disease therapy.

概括炎症在血管痴呆的进展中起重要作用，靶向炎症将为减缓血管痴呆和血管进展的巨大希望和改善认知功能。核苷酸结合寡聚结构域（NOD）样受体蛋白3（NLRP3）炎性体在调节内皮细胞和小胶质细胞引起的炎症。小胶质细胞中的NLRP3表达升高已与血管痴呆的发病机理。抑制小胶质细胞和脑内皮细胞介导的通过靶向异常NLRP3激活的炎症已成为一种新颖，有希望的治疗血管痴呆和其他神经退行性疾病的治疗方法。我们的初步数据表明，AMS-17是一种从磺酰脲化合物中修饰的新分子，通过抑制活性具有针对LPS诱导的小胶质细胞炎症的抗炎作用 nlrp3。此外，AMS-17改善了认知功能并保护神经元免受小鼠血管痴呆模型中的死亡。提出了该建议来研究治疗作用并阐明其作用机理在小鼠中使用血管痴呆模型。我们的目标是为NLRP3开发铅分子具有高选择性，足够的代谢稳定性和低毒性的抑制作用可用于改善血管痴呆的认知结果。如果成功，则铅分子将给出一个新的血管性痴呆和其他神经退行性疾病的有效治疗方法。这该项目的总体影响对于推进脑疾病的药物发现非常重要治疗。