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

描述（由申请人提供）：本R01申请描述了一项阿尔茨海默病（AD）药物发现项目，该项目基于阿尔茨海默病大脑内脂质氧化产物激活特定神经元受体的发现，导致淀粉样蛋白（Ab）肽的产生和积累增加。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，导致淀粉样蛋白前体蛋白（APP）的表达增加，而Ab正是由APP产生的。因此，TP受体阻滞剂有望阻止异前列腺素介导的APP和Ab升高，这一点已被证实，该受体拮抗剂可显著降低已建立的Tg2576 AD小鼠模型中的Ab水平和斑块沉积。尽管这些结果为使用TP受体阻滞剂治疗AD的新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，这限制了它们作为潜在AD治疗药物的用途。因此，我们建议在本申请中开发新的脑渗透型TP受体阻滞剂来治疗AD，其具体目标是：1)合成新的改进的TP受体拮抗剂，并通过一组集中的体外效力和安全性测试评估它们，随后进行小鼠药代动力学测试，以鉴定脑渗透化合物；2)对Aim 1中2-5个最佳候选化合物在正常小鼠体内进行规模化合成和后续测试，以确定其毒理学特征和相关治疗指标；3)评价1-3种化合物在Tg2576转基因AD小鼠模型中安全性和治疗指标最好。这些研究的成功完成将导致一种或多种新的候选药物从一类新的阿尔茨海默病治疗中产生，这些药物将具有减少阿尔茨海默病大脑中Ab肽和老年斑的潜力。

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.