Amyloid-Lowering Small Molecule AB-Binding Agents in AD

AD 中降低淀粉样蛋白的小分子 AB 结合剂

• 批准号: 7130942
• 负责人: WILLIAM E KLUNK
• 金额: $ 45.91万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7130942
• 关键词: Alzheimer' s disease; amyloid proteins; amyloidosis; analog; biological products; brain disorder chemotherapy; combination therapy; cooperative study; drug design /synthesis /production; drug screening /evaluation; genetically modified animals; germ free condition; immunotherapy; laboratory mouse; neuropharmacology; neurotoxicology; nonhuman therapy evaluation; pharmacokinetics; protein binding; small molecule

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.

描述（由申请人提供）：尽管过去 15 年阿尔茨海默病 (AD) 的对症治疗取得了稳步进展，但目前尚无治疗方法可以改变这种疾病的病程。由于淀粉样β (A?) 肽在AD 病理生理学中的关键作用，A?合成、沉积和清除已成为新疗法开发的重要靶点。本申请提出在淀粉样蛋白沉积的 PSAPP 转基因小鼠模型中优化几种先导小分子 Aβ 结合剂 (SMApBA) 的体内抗淀粉样蛋白特性。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显像剂计划的一部分，这些化合物被设计为对 Aβ 具有高亲和力、良好的大脑进入性和特异性标记 Aβ 。体内沉积。体外研究表明，此类化合物具有抗聚集和抗氧化作用，可保护细胞免受Aβ的毒性作用。在 PSAPP 小鼠的初步研究中，几种 SMA?BA 减少了可溶性和不溶性 A?水平降低 50-75%。我们假设这些 SMA?BA 的体内淀粉样蛋白清除作用将与免疫治疗的淀粉样蛋白清除协同作用，因为 SMA?BA 可能会增加总 A? 的比例。驻留在可溶池中，从而产生更多的 A？可通过血管抗体增强外周清除率。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（以及这三种新合成的 24 种类似物中的两种）的开发，使一种化合物可以用于后续的动物毒理学和 I 期人体试验。研究。我们建议通过以下方式做到这一点：1) 将我们的初步抗淀粉样蛋白研究扩展到更多的 PSAPP 小鼠中，并在较大年龄、较长时间和新开发的 SMA?BA 上进行治疗； 2) 对两种最有前途的药物进行剂量反应和口服疗效研究； 3)评估SMA?BA与被动免疫治疗的协同性； 4) 评估两种最有效的先导SMA?BA 的吸收、分布、代谢和消除（ADME）和急性旋转神经毒性，并优化最佳化合物的化学合成，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，我们组建了一个拥有该项目所需额外专业知识的团队，并已经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、分子生物学等方面的专业知识。 淀粉样蛋白生物学、临床试验设计以及临床神经病学和精神病学。