Discovery and Optimization of Triazolopyrimidinone Derivatives as Selective NLRP3 Inflammasome Inhibitors

The NLRP3 inflammasome is a multiprotein complex that facilitates activation and release of the proinflamma-tory cytokines interleukin-1 beta (IL-1 beta) and IL-18 in response to infection or endogenous stimuli. It can be inappropriately activated by a range of danger signals resulting in chronic, low-grade inflammation underlying a multitude of diseases, such as Alzheimer's disease, Parkinson's disease, osteoarthritis, and gout. The discovery of potent and specific NLRP3 inhibitors could reduce the burden of several common morbidities. In this study, we identified a weakly potent triazolopyrimidone hit (1) following an in silico modeling exercise. This was optimized to furnish potent and selective small molecule NLRP3 inflammasome inhibitors. Compounds such as NDT-30805 could be useful tool molecules for a scaffold-hopping or pharmacophore generation project or used as leads toward the development of clinical candidates. Optimization 1 Hit from pharmacophore model PBMC IL-1p ICsc = 70 % at 40 pM NDT-30805 (50) PBMC IL-10 IC50 = 13 nM Good solubility High selectivity

Automated summary

The NLRP3 inflammasome is a multiprotein complex that releases inflammatory cytokines in response to infection or endogenous stimuli. Inappropriately activated NLRP3 inflammasome can lead to chronic, low-grade inflammation underlying various diseases. The discovery of effective NLRP3 inhibitors could alleviate the burden of common diseases.