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

开发用于干预阿尔茨海默病的新型 NLRP3 炎性体抑制剂

• 批准号: 10631193
• 负责人: Shijun Zhang
• 金额: $ 140.33万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631193
• 关键词: 3xTg-AD mouse; AD transgenic mice; Adaptor Signaling Protein; Address; Affinity; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Ames Assay; Animal Disease Models; Animal Model; Binding; Binding Proteins; Binding Sites; Biologic Characteristic; Biological Availability; Biological Products; Biophysics; CASP1 gene; Canis familiaris; Cell Death; Cellular Assay; Cellular Stress; Chemicals; Clinical; Clinical Research; Clinical Trials; Dementia; Dependence; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Evaluation; Family; Formulation; Future; Generations; Goals; IL18 gene; Immunology; In Vitro; Inflammasome; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-1 beta; Investigational Drugs; Lead; Metabolic; Methods; Mus; Natural Immunity; Neurodegenerative Disorders; Neurology; Oral; Oral Administration; Pathogenesis; Permeability; Pharmaceutical Chemistry; Phosphotransferases; Plasma Proteins; Play; Preventive; Production; Property; Proteins; Public Health; Publishing; Rattus; Regimen; Reporting; Research; Rodent; Role; Specificity; Structure-Activity Relationship; Sulfonamides; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxicology; Validation; analog; blood-brain barrier penetration; candidate identification; candidate selection; cell injury; chemical synthesis; clinical candidate; cognitive function; compound 30; cytokine; design; drug development; drug discovery; flexibility; human disease; improved; in silico; in vivo; inhibitor; manufacture; marenostrin; meetings; microbial products; mouse model; multidisciplinary; neuroinflammation; novel; patient response; pharmacologic; pre-clinical; protein complex; receptor; scaffold; scale up; sensor; small molecule; small molecule libraries; therapeutic candidate; therapeutically effective

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.

神经炎症已被认为是阿尔茨海默病发病机制中的重要参与者 疾病（AD）。最近，NOD样受体家族pyrin domain containing 3（NLRP 3）炎性体， 多聚体蛋白复合物，紧密调节先天性免疫反应，已被建议与 在AD发展和进展中的关键作用。NLRP 3炎性体的失调是导致 促炎性白细胞介素（IL）-1β和IL-18的过度产生，最终导致炎性 反应和细胞死亡。因此，NLRP 3炎性体代表了AD的有吸引力的药物靶标，并提供了 承诺提供有效的疾病修饰潜力。在过去的几年里，我们的团队 成功开发了新型小分子NLRP 3炎性体选择性抑制剂（NSIs）。我们最初 报道了具有含磺胺的化学支架的NSIs，并建立了小分子文库 含有超过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 在转基因AD小鼠模型中的第二代领先NSI证明了靶向接合和体内功效， 减少神经炎症并改善认知功能。我们最近的药物化学运动 鉴定具有显著提高的效力和结合亲和力的新的先导国家统计机构。而且我们的 累积的构效关系（SAR）研究已经确定了支架的关键结构特征 以进一步优化。这一建议的核心假设是， 通过设计新的可行类似物，分离有效的口服药物， 具有改善的药代动力学（PK）特性（目标1）的NSIs， NLRP 3炎性体将减轻神经炎症并改善认知功能， 临床前AD动物模型（目标2），将通过临床前研究性新药 （IND）-使研究（目标3）推进到临床研究。对于我们的假设，该应用程序的目标是 完成至少一项候选NSI的临床前IND启动研究，并准备与 FDA和随后的IND申请。为实现我们的目标，提出了三个目标。在目标1中，新类似物 将设计、合成和生物学表征的主要国家科学研究机构，以建立一个动态的药物发现 发展管道。在目标2中，将在不同的研究中检测目标1中选定的NSIs的PK/PD特性。 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IND使能研究，包括GMP生产、啮齿动物和犬的GLP毒理学研究，以及 口服制剂开发，为IND申报和临床试验做准备。该研究建议高度 重要的是，我们正在开发一种新型的国家统计机构，这将为提供新的、 AD是一种目前无法治愈的破坏性神经退行性疾病。