A Novel Small Molecule TNF-alpha Inhibitor as a Disease-Modifying Alzheimer's Disease Drug Treatment

摘要 该提案的目标是开发肿瘤坏死因子α（TNFα）抑制化合物， 治疗阿尔茨海默病（AD）的神经保护药物。目前FDA批准的AD 干预措施是疗效有限的对症治疗，不影响AD病因，或 改变疾病进展的进程。因此，迫切需要一种新的AD治疗 针对AD病理生理学。 最近的研究表明，神经炎性细胞因子TNF-α是AD的关键介质， 相关的神经退行性病变。多项临床前和临床研究表明， TNFα是一种“可药物化”的分子靶点，可改变AD进展的进程。 初步研究表明，我们的先导化合物在体外显示出有效的TNFα抑制作用。 我们的1期SBIR研究表明，我们的小分子TNFα抑制剂 每天口服10个月，显著改善了三转基因小鼠的认知功能。 （3xTg）AD小鼠模型。我们的化合物还调节脑TNFα蛋白水平， AD相关神经病理学研究进展，包括斑块和神经纤维缠结 如通过免疫组织学染色评估的。无发病率、死亡率或任何明显副作用 尽管长期口服每日治疗方案与我们的化合物观察。采取 总之，这些数据有力地表明，我们的先导化合物是一种很好的抗AD药物 候选人拟议的研究是对最近授予的第2阶段SBIR的后续研究， 正在进行几项FDA要求的关键IND研究。拟议的CRP赠款研究将 在2期SBIR研究的基础上进行IND申报。主要目标包括大型动物 安全性毒理学研究和准备与FDA的Pre-IND会议。

ABSTRACT The goal of this proposal is to develop tumor necrosis factor α (TNFα)-inhibiting compounds as neuroprotectant drugs for treating Alzheimer’s disease (AD). Current FDA-approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression. Thus, a critical need exists for a novel AD treatment directed towards AD pathophysiology. Recent studies implicate the neuroinflammatory cytokine TNF-α as a key mediator in AD- associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNFα is a “druggable” molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound shows potent TNFα inhibition in vitro. Our Phase 1 SBIR studies demonstrate that our small molecule TNFα inhibitor administered orally every day for 10 months significantly improved cognitive function in the triple-transgenic (3xTg) AD mouse model. Our compound also modulated brain TNFα protein levels and halted the progress of AD-associated neuropathology including Aß plaques and neurofibrillary tangles as assessed by immunohistological staining. No morbidity, mortality or any obvious side effects were observed despite the long-term oral daily treatment regimen with our compound. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed studies are following up on recently awarded phase 2 SBIR where we are performing several key FDA-required IND studies. The proposed CRP grant studies will build on the phase 2 SBIR studies to lead to an IND submission. Key Aims include large animal safety toxicology studies and preparation for Pre-IND meeting with the FDA.