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: 10428458
• 负责人: Kevin Hodgetts
• 金额: $ 161万
• 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/10428458
• 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; Persons; 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

发现调节神经炎症的药物用于治疗阿尔茨海默病 项目概要/摘要（30行） 阿尔茨海默病（Alzheimer's disease，AD）是老年人痴呆的主要原因。目前，约3600万 全世界有1000万人患有AD，预计到2040年这一数字将增加到约1.2亿。尽管 经过几十年的深入研究，目前只有四种FDA批准的药物可以治疗AD症状。这些 然而，药物不能预防、阻止或减缓疾病的进展。 炎症被认为是Aβ斑块、NFT和AD之间的关键联系。因此，亲- 抗炎性细胞因子可能是治疗AD的一种可行方法。在筛选中识别小分子调节剂 我们鉴定了一种对GABAA和TSPO受体都具有适度亲和力的有希望的先导化合物。 初步的SAR和数据表明，抗炎作用来自两者的结合 GABAA和TSPO的活动。药效学和药代动力学的持续优化 先导化合物的性质将导致显著改善的分子，其具有治疗（i）认知障碍和（ii）认知障碍的潜力。 赤字和（ii）焦虑和侵略的AD。实现这一目标的具体目标是： 目标1。艾提伏辛在两种AD小鼠模型中的体内概念验证研究。艾提伏辛已经证明 在几种神经退行性疾病模型中的有益作用;然而，它没有在小鼠模型中进行测试。 在AD或人类AD患者中。因此，我们将评估艾提伏辛在（i）rTG 4510（Tau）中的功效。 病理学）和（ii）AD的APP/PS1（淀粉样斑块）小鼠模型。 目标二。艾提伏辛新型类似物的药物化学优化和表征。单个 将设计、合成并在生物测定中表征艾提伏辛的对映体类似物。最 将在药物样性质和PK研究中评价有前景的化合物。具有适当PK的化合物 并且脑暴露将进入体内研究以测量靶结合（例如，刺激 小鼠脑中的双烯醇酮）。铅化合物也将进行镇静作用的测试， 镇静剂的作用就不重要了 目标3。先导分子在rTG 4510 AD小鼠模型中的体内功效。我们将评估 在rTG 4510小鼠模型中三种不同剂量的先导化合物（如目的1所述），治疗 将在2个月时开始开始（发病病理学），并在5个月时结束（认知能力下降开始）。目标是 在多个指标上显示出疗效，包括炎症、突触完整性、神经变性、tau蛋白 发病机制、记忆和学习。 目标4。IND前使能研究;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可能妨碍其进一步开发的责任。主角是 在一组工业标准体外DMPK和体外毒性研究（例如，代谢产物抑制 标识和安全面板）。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