Discovery of Drugs that Modulate Neuroinflammation for the treatment of Alzheimer's Disease

发现调节神经炎症治疗阿尔茨海默病的药物

• 批准号: 10052276
• 负责人: Kevin Hodgetts
• 金额: $ 177.02万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10052276
• 关键词: APP-PS1; Affinity; Aggressive behavior; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Animal Model; Anti-Anxiety Agents; Antiinflammatory Effect; Anxiety; Binding; Biological Assay; Brain; Clinical; Cognitive deficits; Data; Dementia; Development; Disease Progression; Disease model; Dose; Drug Kinetics; Elderly; FDA approved; Goals; Human; Impaired cognition; In Vitro; Industry Standard; Inflammation; Inflammatory; Lead; Learning; Link; Measures; Memory; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Pathogenesis; Pathology; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pregnenolone; Property; Research; Risk; Rodent; Safety; Senile Plaques; Solubility; Structure; Symptoms; Synapses; TNF gene; Testing; Toxic effect; Work; analog; aqueous; clinical development; cytokine; design; efficacy evaluation; enantiomer; improved; in vivo; mouse model; neuroinflammation; neuropathology; neurosteroids; novel; pharmacokinetics and pharmacodynamics; receptor; scale up; sedative; small molecule; tau Proteins

Discovery of Drugs that Modulate Neuroinflammation for the Treatment of Alzheimer's Disease Project Summary/Abstract (30 lines) Alzheimer’s disease (AD) is the primary cause of dementia in the elderly. At present, approximately 36 million people worldwide suffer with AD, and that number is expected to increase to about 120 million by 2040. Despite decades of intense research, currently there are only four FDA-approved drugs to treat AD symptoms. These drugs, however, do not prevent, stop or slow the progression of the disease. Inflammation is considered a crucial link between Aβ plaques, NFTs and AD. Therefore, the modulation of pro- inflammatory cytokines may be a viable approach to treat AD. In a screen to identify small molecule modulators of inflammation, we identified a promising lead that has modest affinity for both the GABAA and TSPO receptors. The preliminary SAR and data suggest that the anti-inflammatory effect derives from a combination of both GABAA and TSPO activities. Continued optimization of both the pharmacodynamic and pharmacokinetic properties of the lead will result in a significantly improved molecule that has the potential to treat both (i) cognitive deficits and (ii) anxiety and aggression in AD. The specific aims to achieve this goal are: Aim 1. In vivo proof of concept studies of etifoxine in two mouse models of AD. Etifoxine has demonstrated beneficial effects in several neurodegenerative disease models; however, it was not tested in mouse models of AD or in human AD patients. Therefore, we will evaluate the efficacy of etifoxine in (i) the rTG4510 (Tau pathology) and (ii) the APP/PS1 (amyloid plaque) mouse models of AD. Aim 2. Medicinal chemistry optimization and characterization of novel analogs of etifoxine. Single enantiomer analogs of etifoxine will be designed, synthesized and characterized in biological assays. The most promising compounds will be evaluated in drug-like property and PK studies. Compounds with appropriate PK and brain exposure will advance into in vivo studies to measure target engagement (e.g., stimulation of pregnenolone in mouse brain). Lead compounds also will be tested for sedative effects, and those that have sedative potential will be deprioritized. Aim 3. In vivo efficacy of the lead molecule in the rTG4510 mouse model of AD. We will evaluate the effects of three different doses of the lead compound in the rTG4510 mouse model (as described in Aim 1), Treatment will begin at 2 months (onset pathology), and end at 5 months (start of cognitive decline). The goal is to demonstrate efficacy on multiple measures including inflammation, synaptic integrity, neurodegeneration, tau pathogenesis, memory and learning. Aim 4. Pre-IND enabling studies; scale-up synthesis, multi-species PK, and rodent toxicity. The goal is to determine if the lead compound has any liabilities that would preclude its further development. The lead will be tested in a battery of industry standard in vitro DMPK and in vitro toxicity studies (e.g., CYP inhibition, metabolite identification, and safety panels). Finally, a 10-day, toxicity study will be performed to de-risk the lead compound. 1

发现调节神经炎症治疗阿尔茨海默病的药物 项目摘要/摘要（30 行） 阿尔茨海默病（AD）是老年人痴呆的主要原因。目前，大约有3600万 全世界都有 AD 患者，预计到 2040 年这一数字将增加到约 1.2 亿。 经过数十年的深入研究，目前 FDA 批准的治疗 AD 症状的药物只有四种。这些 然而，药物并不能预防、阻止或减缓疾病的进展。 炎症被认为是 Aβ 斑块、NFT 和 AD 之间的重要联系。因此，亲的调制 炎症细胞因子可能是治疗 AD 的可行方法。在筛选中识别小分子调节剂 炎症的研究中，我们发现了一种有前途的先导化合物，它对 GABAA 和 TSPO 受体都有一定的亲和力。 初步的 SAR 和数据表明，抗炎作用来自于两者的结合 GABAA 和 TSPO 活动。药效学和药代动力学的持续优化 铅的特性将导致显着改善的分子，有可能治疗（i）认知 AD 中的缺陷和 (ii) 焦虑和攻击性。实现这一目标的具体目标是： 目标 1. 在两种 AD 小鼠模型中进行依托福辛的体内概念验证研究。依替福辛已证明 对几种神经退行性疾病模型的有益作用；然而，它没有在小鼠模型中进行测试 AD 或人类 AD 患者。因此，我们将评估依替福辛在 (i) rTG4510（Tau 病理学）和（ii）AD 的 APP/PS1（淀粉样蛋白斑）小鼠模型。 目标 2. 新型依替福辛类似物的药物化学优化和表征。单身的 将设计、合成依替福辛的对映体类似物并在生物测定中进行表征。最 有前景的化合物将在类药特性和药代动力学研究中进行评估。具有适当 PK 的化合物 大脑暴露将进入体内研究，以测量目标参与度（例如，刺激 小鼠大脑中的孕烯醇酮）。还将测试先导化合物的镇静作用，以及那些具有镇静作用的化合物 镇静潜力将被优先考虑。 目标 3. 先导分子在 AD 小鼠 rTG4510 模型中的体内功效。我们将评估效果 rTG4510 小鼠模型中三种不同剂量的先导化合物（如目标 1 中所述），治疗 将于 2 个月时开始（发病病理），并于 5 个月时结束（认知能力开始下降）。目标是 证明对多种指标的功效，包括炎症、突触完整性、神经退行性变、tau 发病机制、记忆和学习。 目标 4. IND 前赋能研究；放大合成、多物种 PK 和啮齿动物毒性。目标是 确定先导化合物是否有任何阻碍其进一步发展的责任。领先将是 在一系列行业标准体外 DMPK 和体外毒性研究（例如 CYP 抑制、代谢物 识别和安全面板）。最后，将进行为期 10 天的毒性研究，以降低先导化合物的风险。 1