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

该R 01申请描述了一种阿尔茨海默病（AD）药物发现计划，该计划基于 发现AD脑内的脂质氧化产物激活确定的神经元受体， 导致淀粉样β（A）肽产生和积累的增加。更具体地说，氧化的 花生四烯酸产物异前列烷2FIII与神经元上的血栓烷A2（TP）受体结合， 导致A所来源的淀粉样前体蛋白（APP）表达增加。 因此，预期TP受体阻断剂可防止异前列腺素介导的APP升高， 这一点已经通过显示该受体的拮抗剂显著降低A水平而得到证实 和斑块沉积。虽然这些结果提供了重要的 为了验证使用TP受体阻滞剂治疗AD的新治疗策略，我们 发现现有的这种靶点的拮抗剂具有较差的血脑屏障穿透性，这限制了它们的作用。 作为潜在的AD治疗方法的有用性。因此，我们在本申请中提出开发新颖的脑- 用于治疗AD的渗透性TP受体阻断剂，其具体目的是：1）合成新的， 改进的TP受体拮抗剂并在一组集中的体外效力和安全性测定中对其进行评价， 随后进行小鼠药代动力学测试，以鉴定脑渗透化合物; 2）进行放大 在正常小鼠中合成和随后测试来自Aim 1的2-5种最佳候选化合物， 测定它们的毒理学特性和相对治疗指数;和3）用 在AD的Tg 2576转基因小鼠模型中的最佳安全性特征和治疗指数。成功 这些研究的完成将产生一种或多种新的候选药物， 因此，本发明提供了将具有减少AD脑中的A肽和老年斑的潜力的治疗剂。

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 (A) peptide production and accumulation. More specifically, the oxidized arachidonic acid product, isoprostane 2FIII, binds to the thromboxane A2 (TP) receptor on neurons and causes an increase in expression of the amyloid precursor protein (APP) from which A is derived. Accordingly, a TP receptor blocker would be expected to prevent isoprostane-mediated elevation of APP and A, and this has been confirmed by showing that an antagonist to this receptor significantly reduces A 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 A peptides and senile plaques in the AD brain.