Discovery of a brain penetrant NLRP3 inflammasome inhibitor that reduces neuropathic pain in mice.

In our continuing campaign to discover novel inhibitors of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3), an emerging drug target that tightly regulates the innate immune responses, a 1H-1,2,3-triazole-4-carboxamide scaffold was designed and optimized. Iterative optimization led to the identification of a lead inhibitor, 22, with an IC50 of 70 nM to suppress the release of interleukin (IL)-1β upon NLRP3 activation. Further in vivo studies supported its selective suppression of the NLRP3 inflammasome. Pharmacokinetic studies of 22 and PET imaging studies employing a F-18 tracer of 22 demonstrated 22 as a brain penetrant with reversible binding kinetics within the CNS. Importantly, treatment of AD patient-derived hiPSC glia cells including microglia and astrocytes and neuropathic pain mice with 22 led to suppression of NLRP3 expression and decreased pain and pain-like behavior, supporting the translational promise of this compound and analogs from this chemotype.