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

用于治疗阿尔茨海默病的脑渗透性血栓烷受体拮抗剂

• 批准号: 8522104
• 负责人: KURT R. BRUNDEN
• 金额: $ 44.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522104
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Arachidonic Acids; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Cell physiology; Cognitive; Data; Deposition; Development; Disease; Disease Progression; Dose; Drug Kinetics; Evaluation; Genetic; Human; In Vitro; Isoprostanes; Lead; Lipids; Mediating; Molecular Target; Mus; Mutation; Nerve Degeneration; Neurons; Pathogenesis; Penetration; Peptides; Performance; Pharmaceutical Preparations; Production; Proteins; Proteolysis; Proteolytic Processing; Relative (related person); Safety; Senile Plaques; Testing; Tg2576; Therapeutic; Therapeutic Index; Thromboxane A2; Thromboxane Receptor; Transgenic Mice; Uncertainty; Validation; base; design; direct application; drug candidate; drug discovery; extracellular; improved; in vitro Assay; in vivo; mouse model; neuropathology; novel; novel therapeutic intervention; novel therapeutics; oxidation; peptide A; presenilin; prevent; programs; protein expression; receptor; scale up; stem

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.

此R01应用程序描述了一个阿尔茨海默病(AD)药物发现计划，该计划基于 发现阿尔茨海默病大脑中的脂质氧化产物激活了一个确定的神经元受体，具有 从而增加淀粉样β(A)多肽的产生和积累。更具体地说，被氧化的 花生四烯酸产物异前列腺素2FIII与神经元上的血栓素A2(TP)受体结合，并 导致A衍生的淀粉样前体蛋白(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APP升高。 A，这一点已经得到证实，该受体的拮抗剂显著降低了A水平 并在已建立的Tg2576阿尔茨海默病小鼠模型中出现斑块沉积。尽管这些结果提供了重要的 使用TP受体阻滞剂治疗AD的新治疗策略的有效性，我们已经 发现现有的这种靶点的拮抗剂血脑屏障穿透性差，这限制了他们的 作为潜在的阿尔茨海默病疗法的有效性。因此，我们在这一应用中建议开发新的、大脑- 渗透性TP受体阻滞剂用于治疗AD，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试中对它们进行评估， 随后进行小鼠药代动力学试验，以鉴定脑渗透化合物；2)进行放大 2-5个最佳候选化合物在正常小鼠体内的合成和后续测试 确定它们的毒理学特征和相关治疗指数；3)评价1-3个化合物 Tg2576转基因AD小鼠模型的最佳安全性和治疗指标。成功者 这些研究的完成将导致一种或多种来自新类别AD的新药候选 治疗将有可能减少AD大脑中的A肽和衰老斑块。