A Novel-designed sulfonylurea compound for Vascular Dementia Therapy

摘要 炎症在血管性痴呆的进展中起着重要作用，并且靶向 炎症将为减缓血管性痴呆的进展和 改善认知功能。核苷酸结合寡聚结构域(NOD)样受体 蛋白3(NLRP3)炎症小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NLRP3表达升高与 血管性痴呆的发病机制。小胶质细胞和脑内皮细胞介导的抑制作用 靶向NLRP3异常激活的炎症已成为一种新的、有前途的 治疗血管性痴呆和其他神经退行性疾病的治疗方法。 我们的初步数据显示，由磺酰基脲化合物修饰而成的新分子AMS-17， 通过抑制活性发挥抗炎作用 NLRP3。此外，AMS-17可改善认知功能，保护神经元免受 小鼠血管性痴呆模型的死亡。 这项建议是为了研究治疗效果并阐明其作用机制。 采用小鼠血管性痴呆模型。我们的目标是开发NLRP3的先导分子 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 改善血管性痴呆的认知结果。如果成功，铅分子将产生一种新的 治疗血管性痴呆和其他神经退行性疾病的有效方法。这个 该项目的总体影响在推进脑部疾病的药物发现方面具有重要意义 心理治疗。

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.