Development of Novel Tetrahydroquinoline Inhibitors of NLRP3 Inflammasome for Potential Treatment of DSS-Induced Mouse Colitis.
Basic Information
ID: ALA4765468
Journal: J Med Chem
Title: Development of Novel Tetrahydroquinoline Inhibitors of NLRP3 Inflammasome for Potential Treatment of DSS-Induced Mouse Colitis.
Authors: Dai Z,Chen XY,An LY,Li CC,Zhao N,Yang F,You ST,Hou CZ,Li K,Jiang C,You QD,Di B,Xu LL
Abstract: The NLRP3 inflammasome is a critical component of innate immunity, which defends internal and external threats. However, inappropriate activation of the NLRP3 inflammasome induces various human diseases. In this study, we discovered and synthesized a series of tetrahydroquinoline inhibitors of NLRP3 inflammasome. Among these analogues, compound 6 exhibited optimal NLRP3 inhibitory activity. In vitro studies indicated that compound 6 directly bound to the NACHT domain of NLRP3 but not to protein pyrin domain (PYD) or LRR domain, inhibited NLRP3 ATPase activity, and blocked ASC oligomerization, thereby inhibiting NLRP3 inflammasome assembly and activation. Compound 6 specifically inhibited the NLRP3 inflammasome activation, but had no effect on the activation of NLRC4 or AIM2 inflammasomes. Furthermore, in the dextran sulfate sodium (DSS)-induced colitis mouse model, compound 6 exhibited significant anti-inflammatory activity through inhibiting NLRP3 inflammasome in vivo. Therefore, our study provides a potent NLRP3 inflammasome inhibitor, which deserves further structural optimization as a novel therapeutic candidate for NLRP3-driven diseases.
CiteXplore: 33332136
DOI: 10.1021/acs.jmedchem.0c01924
Patent ID: ┄