Developing Novel REV-ERB Agonists for the Treatment of Neuroinflammation in Alzheimer's Disease

阿尔茨海默病(AD)是一种进行性神经退行性疾病，其临床特征包括 记忆力丧失、认知障碍和痴呆症。广告影响了500多万美国人，位居第六 死亡原因；随着美国老龄化人口的增加，这些数字将大幅上升。鉴于持续的 AD药物在临床试验中的失败和争议，寻找新的靶点以开发有效的药物至关重要 阿尔茨海默病的治疗。 一种得到文献支持的新的潜在治疗方法是矫正异常的神经胶质细胞 导致神经元变性和AD进展的激活和神经炎症。佩拉戈斯制药公司 旨在通过靶向核受体和转录抑制因子rev-erb来减少神经炎症 Pelagos联合创始人兼核受体专家托马斯·伯里斯对新型靶子进行了广泛的研究， 博士学位。REV-ERB在大脑中高度表达，并作为转录抑制因子对负性 调节多种炎性成分在小胶质细胞中的表达，尤其是NLRP3炎症体 以及促炎细胞因子，如IL-6、IL-1和IL-18。在多种体外和体内AD模型中，Rev- 使用工具化合物的ERB激动剂可以减少神经炎症，防止记忆丧失。 佩拉戈斯现在正在开发第一种临床上可行的小分子激动剂，靶向REV-ERB 抑制神经炎症，治疗AD。靶向REV-ERB抑制神经炎症 NLRP3炎症体表达和随后的形成是一种创新的方法，具有巨大的 有可能减轻症状，有效减轻与AD相关的负担。我们的方法是独特的- 竞争对手的目标是单个炎性小体组件，这种方法可能会导致公正 抑制，效果有限，并增加了负面反弹效应的可能性。通过瞄准上游 调节炎症体和细胞因子在小胶质细胞的表达，我们可能会恢复炎症性表达 将成分降至基础水平，并在较长时间内限制慢性炎症。 此第一阶段SBIR的目标是从从我们的化合物衍生的候选化合物中选择一个主要候选者 专有支架(目标1)，并在体外和体内建立多个安全和有效的概念验证 神经炎症和AD模型(目标2)。我们将采取系统的成本效益和时间效益的方法来 基于DMPK属性和功效选择最佳化合物会导致良好建立的模型， 从高通量分析开始筛选多种化合物，以长期转基因动物结束 模型来评估最好的1个化合物。这一第一阶段提案的产品将是一种口服生物利用度较低的 分子REV-ERB激动剂，具有良好的PK/PD，可通过血脑屏障降低 阿尔茨海默病模型的神经炎症。成功完成这一阶段的第一阶段将使佩拉戈斯提高 完成长期安全性和有效性分析并启动IND研究所需的资金。

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease with clinical hallmarks such as memory loss, cognitive impairment, and dementia. AD affects over 5 million American and is the 6th leading cause of death; these numbers will rise dramatically as the US aging population increases. Given the continued failures and controversies of AD drugs in clinical trials, it is critical to identify novel targets to develop effective therapies for AD. One novel potential therapeutic approach that is supported by the literature is to correct the aberrant glial activation and neuroinflammation that contribute to neuronal degeneration and AD progression. Pelagos Pharma aims to reduce neuroinflammation by targeting the nuclear receptor and transcriptional repressor REV-ERB, a novel target has been extensively studied by Pelagos co-founder and nuclear receptor expert Thomas Burris, PhD. REV-ERB is highly expressed in the brain and functions as a transcriptional repressor to negatively regulate expression of multiple inflammatory components in microglia, particularly the NLRP3 inflammasome and pro-inflammatory cytokines such as IL-6, IL-1, and IL-18. In multiple in vitro and in vivo AD models, REV- ERB agonism with tool compounds reduces neuroinflammation and protects against memory loss. Pelagos is now developing the first clinically-viable small molecule agonists that target REV-ERB to suppress neuroinflammation and treat AD. Targeting REV-ERB to suppress neuroinflammation by inhibiting NLRP3 inflammasome expression and subsequent formation is an innovative approach that has tremendous potential to reduce symptoms and effectively reduce the burdens associated with AD. Our approach is unique - competitors are targeting individual inflammasome components, an approach that may result in impartial suppression, limited efficacy, and increased potential for negative rebound effects. By targeting the upstream regulator of inflammasome and cytokine expression in microglia, we may return expression of inflammatory components to a basal level and limit chronic inflammation for a prolonged period. The goal of this Phase I SBIR is to select a lead candidate from a shortlist of compounds derived from our proprietary scaffold (Aim 1) and establish safety and efficacy proof-of-concept in multiple in vitro and in vivo neuroinflammation and AD models (Aim 2). We will take a systematic cost- and time-effective approach to selecting the optimal compound based on DMPK properties and efficacy results in well-established models, starting with high-throughput assays to screen multiple compounds and ending with long-term transgenic animal models to assess the best 1 compound. The product of this Phase I proposal will be an orally bioavailable small molecule REV-ERB agonist with favorable PK/PD that can cross the blood brain barrier to reduce neuroinflammation in AD models. Successful completion of this phase I will position Pelagos to raise the necessary capital to complete long-term safety and efficacy assays and initiate IND-enabling studies.