Brain-Penetrant Thromboxane Receptor Antagonists for Alzheimer's Disease Therapy

描述(由申请人提供)：这份R01申请描述了一项阿尔茨海默病(AD)药物发现计划，该计划基于这样的发现：AD大脑中的一种脂质氧化产物激活已确定的神经元受体，从而增加淀粉样β蛋白(Ab)多肽的产生和积累。更具体地说，氧化的花生四烯酸产物异前列腺素2FaIII与神经元上的血栓素A2(TP)受体结合，导致产生抗体的淀粉样前体蛋白(APP)表达增加。因此，TP受体阻滞剂有望阻止异前列腺素介导的APP和Ab的升高，这一点已被证实，该受体的拮抗剂显著降低了已建立的Tg2576 AD小鼠模型中的Ab水平和斑块沉积。虽然这些结果为使用TP受体阻滞剂治疗AD这一新的治疗策略提供了重要的验证，但我们发现现有的针对该靶点的拮抗剂具有较差的血脑屏障穿透性，限制了它们作为潜在AD治疗药物的有效性。因此，我们建议在这项应用中开发用于治疗AD的新型、脑穿透性TP受体阻滞剂，其具体目的是：1)合成新的、改进的TP受体拮抗剂并在一系列集中的体外效力和安全性分析中对它们进行评估，随后进行小鼠药代动力学测试，以确定脑渗透化合物；2)对来自Aim 1的2-5个最佳候选化合物进行放大合成并随后在正常小鼠身上进行测试，以确定它们的毒理学特征和相关治疗指数；以及3)在Tg2576转基因AD小鼠模型中评估具有最佳安全性和治疗指数的1-3个化合物。这些研究的成功完成将导致一种或多种来自新一类AD治疗药物的新药候选，这些药物将有可能减少AD大脑中的抗体多肽和老年斑。 公共卫生相关性：本R01申请中提出的研究旨在开发一类治疗阿尔茨海默病(AD)的新药。如果成功，这些药物可能有能力减缓AD的进展和/或改善这种疾病患者的认知表现。

DESCRIPTION (provided by applicant): This R01 application describes an Alzheimer's disease (AD) drug discovery program that is based on the discovery that a lipid oxidation product within the AD brain activates a defined neuronal receptor, with a resulting increase of amyloid beta (Ab) peptide production and accumulation. More specifically, the oxidized arachidonic acid product, isoprostane 2FaIII, binds to the thromboxane A2 (TP) receptor on neurons and causes an increase in expression of the amyloid precursor protein (APP) from which Ab is derived. Accordingly, a TP receptor blocker would be expected to prevent isoprostane-mediated elevation of APP and Ab, and this has been confirmed by showing that an antagonist to this receptor significantly reduces Ab levels and plaque deposition in the established Tg2576 mouse model of AD. Although these results provide important validation of a new therapeutic strategy of using TP receptor blockers for the treatment of AD, we have discovered that existing antagonists to this target have poor blood-brain barrier penetration that limits their usefulness as potential AD therapeutics. Accordingly, we propose in this application to develop novel, brain- penetrant TP receptor blockers for the treatment of AD, with the specific aims of: 1) synthesizing new, improved TP receptor antagonists and evaluating them in a focused set of in vitro potency and safety assays, followed by mouse pharmacokinetic testing, to identify brain-penetrant compounds; 2) conducting scale-up synthesis and subsequent testing of the 2-5 best candidate compounds from Aim 1 in normal mice to determine their toxicological profiles and relative therapeutic indices; and 3) evaluating the 1-3 compounds with the best safety profiles and therapeutic indices in the Tg2576 transgenic mouse model of AD. The successful completion of these studies will result in one or more novel drug candidates from a new class of AD therapeutics that will have the potential of decreasing Ab peptides and senile plaques in the AD brain. PUBLIC HEALTH RELEVANCE: The studies proposed within this R01 application are directed toward the development of a new class of drugs for the treatment of Alzheimer's disease (AD). If successful, such drugs might have the ability to slow AD progression and/or improve the cognitive performance of those with this disease.