Design and Discovery of Novel NLRP3 Inhibitors and PET Imaging Radiotracers Based on a 1,2,3-Triazole-Bearing Scaffold

作者：Yiming Xu, Yulong Xu, Savannah Biby, Baljit Kaur, Yan Liu, Frederick A. Bagdasarian, Hsiao‐Ying Wey, Rudolph E. Tanzi, Can Zhang, Changning Wang, Shijun Zhang · 发表于：Journal of Medicinal Chemistry · 年份：2023 · DOI：10.1021/acs.jmedchem.3c01782 · 被引用次数：14 · 研究领域：Inflammasome and immune disorders、Tryptophan and brain disorders、Heme Oxygenase-1 and Carbon Monoxide

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 8 as a potent (IC 50: 0.55 ± 0.16 μM), selective, and direct NLRP3 inhibitor. Positron emission tomography (PET) imaging studies of [ 11 C] 8 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.