Development of NLRP3 inflammasome inhibitors for intervening in Alzheimer's disease

神经炎症被认为是阿尔茨海默氏症发病机制中的一个重要因素 疾病(AD)。最近，包含3(NLRP3)炎症体的NOD样受体家族吡咯结构域，a 紧密调节先天免疫反应的多聚体蛋白复合体，已被认为与 在阿尔茨海默病的发展和进展中的关键作用。NLRP3炎症小体的调节失调是导致 促炎因子IL-1β和IL-18的过度产生，最终导致炎症 反应和细胞死亡。因此，NLRP3炎症体代表了治疗AD的有吸引力的药物靶点，并提供了 承诺提供有效的疾病改善潜力。在过去的几年里，我们的团队 成功开发了新型小分子NLRP3炎性小体选择性抑制剂(NSI)。我们原本 报道了含有磺胺类化学支架的NSI，并建立了小分子文库 含有200种具有不同生物学特性的化合物。我们的第一个概念验证研究 转基因AD小鼠模型中的代铅NSI显示出靶向结合和体内疗效 减少神经炎症，改善认知功能。我们最近的药物化学活动导致了 新的铅NSI的鉴定具有显著提高的效力和结合亲和力。此外，我们的 累积的结构-活性关系(SAR)研究确定了支架的关键结构特征 进行进一步的优化。这一提议的中心假设是，目前两个国家的结构优化 临床前先导NSI将通过设计新的可行的类似物和分离有效的和口服的可用药来实现 具有改进的药代动力学(PK)特性的NSIS(目标1)，以及对 我们的NSI开发的NLRP3炎症体将减轻神经炎症并改善认知功能 临床前AD动物模型(AIM 2)，将通过临床前研究新药进一步评估 (IND)-使研究(目标3)进入临床研究。对于我们的假设，此应用程序的目标是 完成至少一项候选NSI的临床前IND使能研究，并准备与 FDA和随后的IND文件。为了实现我们的目标，我们提出了三个目标。在目标1中，新的类比 将对NSI进行设计、合成和生物学表征，以建立一个动态的药物发现 和开发流水线。在目标2中，从目标1中选择的NSI将在各种情况下进行PK/PD特性测试 动物模型包括AD小鼠模型。在目标3中，从目标2中确定的最佳候选NSI将是 接受包括GMP生产、啮齿动物和狗的GLP毒理学研究在内的支持IND的研究，以及 开发口服制剂，为IND备案和临床试验做准备。拟议中的研究具有很高的 意义重大，因为我们正在开发一类新的NSI，这将提供巨大的前景，以提供新颖和 阿尔茨海默病是一种毁灭性的神经退行性疾病，目前尚无治愈方法。

Neuroinflammation has been recognized as an essential player in the pathogenesis of Alzheimer’s disease (AD). Recently, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multimeric protein complex that tightly regulates the innate immune responses, has been suggested with critical roles in AD development and progression. Dysregulation of the NLRP3 inflammasome is responsible for the over production of pro-inflammatory interleukin (IL)-1β and IL-18, ultimately leading to inflammatory responses and cell death. Thus, NLRP3 inflammasome represents an attractive drug target for AD and offers promise to provide effective disease modifying potential. Over the past several years, our team has successfully developed novel small molecule NLRP3 inflammasome selective inhibitors (NSIs). We originally reported NSIs with sulfonamide containing chemical scaffolds, and have established a small molecule library containing > 200 compounds with various biological characteristics. Proof of concept studies of our 1st generation lead NSI in transgenic AD mouse models demonstrated target engagement and in vivo efficacy to reduce neuroinflammation and improve cognitive functions. Our recent medicinal chemistry campaign led to the identification of new lead NSIs with significantly improved potency and binding affinity. Furthermore, our accumulated structure-activity relationship (SAR) studies have identified key structural features of the scaffolds for further optimization. The central hypothesis of this proposal is that structural optimization of the current two preclinical lead NSIs will be achieved by designing new viable analogs and isolating potent and orally available NSIs with improved pharmacokinetic (PK) properties (Aim 1), and that pharmacological suppression of the NLRP3 inflammasome by our NSIs will mitigate neuroinflammation and improve cognitive functions in preclinical AD animal models (Aim 2), which will be further evaluated by preclinical Investigational New Drug (IND)-enabling studies (Aim 3) to advance to clinical studies. For our hypothesis, the goal of this application is to accomplish preclinical IND-enabling studies on at least one candidate NSI and prepare for a meeting with the FDA and subsequent IND filing. Three aims are proposed to achieve our objectives. In Aim 1, new analogs of the lead NSIs will be designed, synthesized and biologically characterized to build a dynamic drug discovery and development pipeline. In Aim 2, selected NSIs from aim 1 will be tested for PK/PD properties in various animal models including AD mouse models. In aim 3, the top candidate NSI identified from Aim 2 will be subjected to IND-enabling studies including GMP production, GLP toxicology studies in rodents and dogs, and oral formulation development to prepare for IND filing and clinical trials. The proposed research is highly significant because we are developing a novel class of NSIs that will offer great promise to provide novel and effective therapeutics for AD, a devastating neurodegenerative disorder without cure currently.