NADPH-oxidase 2 inhibitors for cardiovascular indications

用于心血管适应症的 NADPH-氧化酶 2 抑制剂

• 批准号: 10691127
• 负责人: Anton Simeonov
• 金额: $ 25.96万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10691127
• 关键词: Atherosclerosis; Biochemical; Biological Assay; Blood Platelets; Cardiovascular system; Carotid Artery Diseases; Cell Culture Techniques; Chronic Granulomatous Disease; Endothelial Cells; Enzymes; Exhibits; Generations; Genes; Goals; Hand; Immune System Diseases; Investigation; Modeling; Mutation; NADPH Oxidase; Patients; Phagocytes; Pharmaceutical Chemistry; Property; Reactive Oxygen Species; Reporting; Research; Structure; improved; inhibitor; loss of function; novel strategies; protein protein interaction; small molecule inhibitor

The goal of this project is to identify small molecule inhibitors of NOX2 activity as a strategy for counteracting atherosclerosis. During this period, the research team screened tens of thousands of small molecules for inhibitors of NOX2 activity. Hits were cherrypicked and validated for activity, and a set of biochemical assays and cell culture models will the further utilized to remove compounds that possess non-specific or undesirable activities. Compounds with promising activity profiles will be considered for advancement to medicinal chemistry for structure activity-guided optimization, and for further investigation in advanced models. We optimized a known NOX-2 inhibitor to improve the ADME and PK properties. The synthesized compounds currently being analyzed in collaborators hand. The collaborators are working on developing a new assay to target protein-protein interaction of the NOX-2 enzyme, a new approach. The project team is currently optimizing a chemotype reported from GSK. A focussed medicinal chemistry effort in ongoing.

该项目的目标是确定 NOX2 活性的小分子抑制剂作为对抗动脉粥样硬化的策略。在此期间，研究小组筛选了数以万计的NOX2活性抑制剂小分子。精选并验证活性，并且将进一步利用一组生化测定和细胞培养模型来去除具有非特异性或不良活性的化合物。具有有前途的活性特征的化合物将被考虑推进药物化学以进行结构活性引导的优化，并在高级模型中进行进一步研究。我们优化了一种已知的 NOX-2 抑制剂，以改善 ADME 和 PK 特性。目前正在合作者手中分析合成的化合物。合作者正在开发一种新的检测方法，以 NOX-2 酶的蛋白质-蛋白质相互作用为目标，这是一种新方法。该项目团队目前正在优化葛兰素史克报告的化学型。正在进行的集中药物化学工作。