Development of selective NLRP3 inflammasome inhibitors

The NLRP3 inflammasome is one of the most attractive drug targets today because of the wide range of possible therapeutic applications, as highlighted in previous chapters. Both industry and academia are seeking to develop selective NLRP3 inhibitors for use in the treatment of local, systemic peripheral, and central nervous system diseases. Several strategies can be used to block NLRP3 signaling. The NLRP3 signaling pathway can be inhibited by interfering upstream with priming processes, by using molecules that can modulate cellular mechanisms that regulate posttranslational modifications of NLRP3, or by blocking protein–protein interactions. However, currently, most efforts are focused on developing compounds that directly bind to and inhibit the NLRP3 sensor protein, thereby inhibiting NLRP3 oligomerization and assembly. In this chapter, a description of such compounds will be given from a medicinal chemistry perspective. Specifically, this chapter will address classes of compounds that have been rationally discovered and modulated and does not include compounds discovered by screening large libraries or from natural product extracts unless they have been used as lead compounds for the development of a specific and extensively studied class of NLRP3 inhibitors.