State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, China.
Bioorg Med Chem Lett. 2020 Apr 1;30(7):127021. doi: 10.1016/j.bmcl.2020.127021. Epub 2020 Feb 6.
Aberrant activation of NLRP3 inflammasome is present in a subset of acute and chronic inflammatory diseases. The NLRP3 inflammasome has been recognized as an attractive therapeutic target for developing novel and specific anti-inflammatory inhibitors. Cellular structure-activity relationship-guided optimization resulted in the identification of 4-oxo-2-thioxo-thiazolidinone derivative 9 as a selective and direct small-molecule inhibitor of NLRP3 with IC of 2.4 μM, possessing favorable ex vivo and in vivo pharmacokinetic properties. Compound 9 may represent a lead for the development of anti-inflammatory therapeutics for treating NLRP3-driven diseases.
NLRP3 炎性小体的异常激活存在于一部分急性和慢性炎症性疾病中。NLRP3 炎性小体已被认为是开发新型、特异抗炎抑制剂的一个有吸引力的治疗靶点。基于细胞结构-活性关系的优化，鉴定出 4-氧代-2-硫代-噻唑烷酮衍生物 9 是 NLRP3 的选择性和直接小分子抑制剂，IC 为 2.4μM，具有良好的体外和体内药代动力学特性。化合物 9 可能代表了一种用于治疗 NLRP3 驱动疾病的抗炎治疗药物的先导化合物。
