Amyloid-Lowering Small Molecule AB-Binding Agents in AD

描述（由申请人提供）：尽管在过去15年中阿尔茨海默病（AD）的对症治疗取得了稳步进展，但目前还没有改变这种疾病病程的治疗方法。由于淀粉样蛋白β（A？）肽在AD病理生理中的作用，A？合成、沉积和清除已成为开发新疗法的重要靶点。本申请提出优化几种先导小分子A？-结合剂（SMApBA）在淀粉样蛋白沉积的PSAPP转基因小鼠模型中的作用。这些试剂是第三代和第四代刚果红衍生物，其结构类似于天然产物姜黄素。作为开发体内淀粉样蛋白成像剂计划的一部分，这些化合物被设计为对A？具有高亲和力，很好的大脑入口，特别标注A在体内沉积。体外研究表明，这类化合物具有抗聚集和抗氧化作用，并保护细胞免受A？的毒性作用。在PSAPP小鼠的初步研究中，几个SMA？BAs减少可溶性和不溶性A？50 - 75%的水平。我们假设这些SMA的体内淀粉样蛋白清除作用？BA将通过免疫治疗与淀粉样蛋白清除合作，因为SMA？BAs可能会增加总A的比例？存在于可溶性池中，从而使更多的A？可用于增强血管抗体的外周清除。在本申请中，我们建议完成三种目前最有前途的先导化合物（以及这三种化合物的24种新合成类似物中的两种）的开发，其中一种化合物已准备好用于随后的动物毒理学和I期人体研究。为此，我们建议：1）在更大数量的PSAPP小鼠中扩展我们的初步抗淀粉样蛋白研究，在较老的年龄，更长的时间和新开发的SMA治疗？BA; 2）进行剂量反应和口服两种最有前途的药物的疗效研究; 3）评估SMA？BA和被动免疫治疗;和4）评估的吸收，分布，代谢和消除（ADME）和急性转棒神经毒性的两个最有效的铅SMA？并优化化学合成的最佳化合物，为GMP生产做准备。基于生产人类淀粉样蛋白成像PET示踪剂匹兹堡化合物-B（PIB）的药物开发专业知识，我们组建了一个具有该项目所需额外专业知识的团队，并已启动了本申请中提出的类型的研究。该团队结合了医学和放射化学，神经药理学，药代动力学和药物代谢，组织病理学，分子生物学， 淀粉样蛋白生物学、临床试验设计、临床神经病学和精神病学。

DESCRIPTION (provided by applicant): Despite steady progress over the past 15 years on the symptomatic treatment of Alzheimer's disease (AD), there is currently no treatment that modifies the course of this disease. Because of the key role of the amyloid-beta (A?) peptide in the pathophysiology of AD, A? synthesis, deposition and clearance have become important targets for the development of new therapies. This application proposes to optimize the in vivo anti-amyloid properties of several lead small molecule A?-binding agents (SMApBAs) in the PSAPP transgenic mouse model of amyloid deposition. These agents are third and fourth generation Congo red derivatives that structurally resemble the natural product, curcumin. As part of a program to develop in vivo amyloid imaging agents, these compounds were designed to have high affinity for A?, good brain entry, and specifically label A? deposits m vivo. In vitro studies have shown that this class of compounds possesses anti-aggregation and anti-oxidant effects and protects cells from toxic actions of A?. In preliminary studies with PSAPP mice, several SMA?BAs reduced soluble and insoluble A? levels by 50-75%. We hypothesis that the in vivo amyloid-clearing effect of these SMA?BAs will be cooperative with amyloid clearance by immunotherapy because the SMA?BAs may increase the proportion of total A? that resides in the soluble pool, thus making more A? available for enhanced peripheral clearance by vascular antibodies. In this application, we propose to complete the development of the three currently most promising lead compounds (and two out of a group of 24 newly synthesized analogs of these three) to the point where one compound is ready for subsequent animal toxicology and phase I human studies. We propose to do this by: 1) extending our preliminary anti-amyloid studies in larger numbers of PSAPP mice, treated at older ages, for longer periods of time and with newly developed SMA?BAs; 2) performing dose-response and oral efficacy studies of the two most promising agents; 3) assessing the cooperativity of SMA?BA and passive immunization treatment; and 4) assessing the absorption, distribution, metabolism and elimination (ADME) and acute rotorod neurotoxicity of the two most effective lead SMA?BA's and optimizing the chemical synthesis of the best compound in preparation for GMP production. Building on the drug development expertise that produced the human amyloid imaging PET tracer Pittsburgh Compound-B (PIB), we have assembled a team with the additional expertise required for this project and have already initiated studies of the type proposed in this application. This team combines expertise in medicinal and radiochemistry, neuropharmacology, pharmacokinetics and drug metabolism, histopathology, molecular biology of amyloid, clinical trial design and clinical neurology and psychiatry.