Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, United States.
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, United States.
Eur J Med Chem. 2022 Aug 5;238:114468. doi: 10.1016/j.ejmech.2022.114468. Epub 2022 May 21.
NLRP3 inflammasome dysregulation has been observed in many human diseases including neurodegenerative disorders. Thus, development of small molecule inhibitors targeting this protein complex represents a promising strategy to achieve disease intervention. In our continuing efforts to develop NLRP3 inhibitors, a recently identified lead inhibitor, YQ128, was further modified and optimized. The structure-activity relationship studies of this lead compound suggested its flexibility for structural modifications while the sulfonamide and benzyl moiety demonstrated being important for selectivity. Additionally, the systematic SAR studies also provided insights for designing NLRC4 and AIM2 inflammasome inhibitors. A new lead inhibitor, 19, was identified with improved potency (IC: 0.12 ± 0.01 μM) and binding affinity (K: 84 nM). Further characterization of this lead compound using wild type and nlrp3 mice confirmed its in vivo selective target engagement. PET studies using a radiotracer based on the structure of 19 also demonstrated its improved brain penetration compared to previous lead compounds. These results strongly encourage further testing of 19 in disease models.
NLRP3 炎性小体失调已在许多人类疾病中观察到，包括神经退行性疾病。因此，开发针对该蛋白复合物的小分子抑制剂是实现疾病干预的一种很有前途的策略。在我们继续开发 NLRP3 抑制剂的过程中，最近鉴定出的先导抑制剂 YQ128 进一步被修饰和优化。该先导化合物的构效关系研究表明，其结构具有可修饰性，而磺酰胺和苄基部分则显示出对选择性的重要性。此外，系统的 SAR 研究也为设计 NLRC4 和 AIM2 炎性小体抑制剂提供了思路。鉴定出一种新的先导抑制剂 19，其活性（IC：0.12±0.01μM）和结合亲和力（K：84nM）得到改善。使用野生型和 nlrp3 小鼠对该先导化合物进行进一步表征，证实了其在体内选择性的靶标结合。基于 19 结构的放射性示踪剂的 PET 研究也表明，与以前的先导化合物相比，它的脑穿透性得到了改善。这些结果强烈鼓励在疾病模型中进一步测试 19。
