Design, Synthesis and Evaluation of Oxazaborine Inhibitors of the NLRP3 Inflammasome. (5th February 2018) - Baldwin, Alex G.
Abstract: The NLRP3 inflammasome is an important regulator of the sterile inflammatory response, and its activation by host‐derived sterile molecules leads to the intracellular activation of caspase‐1, processing of the pro‐inflammatory cytokines interleukin‐1β (IL‐1β)/IL‐18, and pyroptotic cell death. Inappropriate activation of NLRP3 drives a chronic inflammatory response and is implicated in several non‐communicable diseases, including gout, atherosclerosis, type II diabetes and Alzheimer's disease. In this study, we report the design, synthesis and biological evaluation of novel boron compounds (NBCs) as NLRP3 inflammasome inhibitors. Structure–activity relationships (SAR) show that 4‐fluoro substituents on the phenyl rings retain NLRP3 inhibitory activity, whereas more steric and lipophilic substituents diminish activity. Loss of inhibitory activity is also observed if the CCl3 group on the oxazaborine ring is replaced by a CF3 group. These findings provide additional understanding of the NBC series and will aid in the development of these NLRP3 inhibitors as tool compounds or therapeutic candidates for sterile inflammatory diseases. Abstract : A NOD to boron : NLRP3 is a central regulator of sterile inflammation, and its overactivation contributes to the progression of several important diseases. It is therefore a therapeutic target for the treatment of sterile inflammatory disease. Structure–activity relationship (SAR) analysis of a series of oxazaborine small molecules that inhibit NLRP3‐dependent IL‐1β release are reported, the results of which will aid the development of this new class of boron‐based NLRP3 inflammasome inhibitors.