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.
Highlights
Sterile inflammation is a host-driven immune response to injury in the absence of infection.[1]
The synthesis of oxazaborine derivatives containing electron-donating substituents (R = R1 = 4-OMe, 4-NMe2, Scheme 1) were attempted, we found that the bromine-magnesium (Br-Mg) exchange reaction of aryl bromides with B(OMe)3 was highly dependent on aromatic ring substitution
As we had previously reported that only electron-withdrawing substituents at this position were effective NLRP3 inhibitors,[26] we proposed that substituting CCl3 for a CF3 group would test the importance of lipophilicity whilst retaining similar electron-withdrawing propwww.chemmedchem.org
Summary
Synthesis and Evaluation of Oxazaborine Inhibitors of the NLRP3 Inflammasome. 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 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
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