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: 10654599
• 负责人: Kevin Hodgetts
• 金额: $ 150.08万
• 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/10654599
• 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; Drug Modulation; 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; pre-IND studies; 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

治疗阿尔茨海默病的调节神经炎症药物的发现 项目摘要/摘要(30行) 阿尔茨海默病(AD)是导致老年人痴呆的主要原因。目前，大约有3600万 全世界的人都患有阿尔茨海默病，预计到2040年，这一数字将增加到约1.2亿。尽管 经过几十年的紧张研究，目前只有四种FDA批准的药物可以治疗AD症状。这些 然而，药物并不能预防、阻止或减缓疾病的发展。 炎症被认为是Aβ斑块、NFT和AD之间的关键联系。因此，PRO-2的调制。 在fl中，炎性细胞因子可能是治疗AD的可行方法。在屏幕上识别小分子调节器 在炎症方面，我们发现了一种有希望的先导，它对GABAA和TSPO受体都有适度的亲和力。 初步的SAR和数据表明，抗炎作用来自两者的结合 GABAA和TSPO活动。药效学和药动学的持续优化 铅的性质将导致一种显著改进的分子，它有可能治疗以下两种情况：(I)认知 缺陷和(Ii)AD的焦虑和攻击性。实现这一目标的具体目标是： 目的1.在两种阿尔茨海默病小鼠模型上进行艾司福辛的体内概念验证。依替福辛已经证明 在几种神经退行性疾病模型中的有益效果；然而，它没有在 AD或在人类AD患者中。因此，我们将评估依福辛在(I)rTg4510(Tau)中的疗效 病理)和(Ii)AD的APP/PS1(淀粉样斑块)小鼠模型。 目的2.新的乙氧福辛类似物的药物化学优化及表征。单人 乙氧福辛的对映体类似物将设计、合成并在生物测定中进行表征。最多的 有希望的化合物将在类药物性质和PK研究中进行评估。具有适当pk的化合物 而脑暴露将进入体内研究，以测量目标参与(例如，刺激 小鼠脑内孕烯醇酮)。还将测试先导化合物的镇静作用，以及那些具有 镇静的潜力将被剥夺。 目的3.铅分子对rTg4510小鼠AD模型的体内效应。我们将评估效果 在rTg4510小鼠模型中使用三种不同剂量的先导化合物(如目标1所述)，治疗 开始于2个月(发病病理)，结束于5个月(开始认知衰退)。我们的目标是 显示多种措施的有效性，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。 目的4.前IND使能研究；放大合成、多物种PK和啮齿动物毒性。我们的目标是 确定先导化合物是否有任何可能阻碍其进一步发展的负债。领头羊将是 在一组行业标准的体外DMPK和体外毒性研究中进行测试(例如，CYP抑制、代谢物 身份识别和安全面板)。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