Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
J Med Chem. 2024 Jan 11;67(1):555-571. doi: 10.1021/acs.jmedchem.3c01782. Epub 2023 Dec 27.
The NOD-like receptor (NLR) family pyrin-domain-containing 3 (NLRP3) inflammasome, an essential component of the innate immune system, has been emerging as a viable drug target and a potential biomarker for human diseases. In our efforts to develop novel small molecule NLRP3 inhibitors, a 1-(5-chloro-2-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole scaffold was designed via a rational approach based on our previous leads. Structure-activity relationship studies and biophysical studies identified a new lead compound as a potent (IC: 0.55 ± 0.16 μM), selective, and direct NLRP3 inhibitor. Positron emission tomography (PET) imaging studies of [C] demonstrated its rapid and high brain uptake as well as fast washout in mice and rhesus macaque. Notably, plasma kinetic analysis of this radiotracer from the PET/magnetic resonance imaging studies in rhesus macaque suggested radiometabolic stability. Collectively, our data not only encourage further studies of this lead compound but also warrant further optimization to generate additional novel NLRP3 inhibitors and suitable central nervous system PET radioligands with translational promise.
NOD 样受体 (NLR) 家族包含 pyrin 结构域的 3 (NLRP3) 炎症小体，作为先天免疫系统的重要组成部分，已成为可行的药物靶点和人类疾病的潜在生物标志物。在我们努力开发新型小分子 NLRP3 抑制剂的过程中，根据我们之前的先导化合物，通过合理的方法设计了 1-(5-氯-2-甲氧基苄基)-4-苯基-1H-1,2,3-三唑骨架。结构-活性关系研究和生物物理研究确定了一种新的先导化合物 ，作为一种有效的（IC：0.55 ± 0.16 μM）、选择性和直接的 NLRP3 抑制剂。[C]的正电子发射断层扫描 (PET) 成像研究表明，其在小鼠和恒河猴中具有快速和高的脑摄取以及快速洗脱。值得注意的是，从恒河猴的 PET/磁共振成像研究中的血浆动力学分析表明该示踪剂具有放射性代谢稳定性。总的来说，我们的数据不仅鼓励对该先导化合物进行进一步研究，还需要进一步优化以产生额外的新型 NLRP3 抑制剂和具有转化潜力的合适的中枢神经系统 PET 放射性配体。
