Discovery of novel 2,3,5-trisubstituted pyridine analogs as potent inhibitors of IL-1β via modulation of the p38 MAPK signaling pathway

Interleukin-1b is a central mediator of innate immune responses and inflammation. It plays a key role in a wide variety of pathologies, ranging from autoinflammatory diseases to metabolic syndrome and malignant tumors. It is well established that its inhibition results in a rapid and sustained reduction in disease severity, underlining the importance of having a repertoire of drugs of this class. At present, there are only three interleukin-1 beta blockers approved in the clinic. All of them are biologics, requiring parenteral administration and resulting in expensive treatments. In an exercise to identify small molecule allosteric inhibitors of MAP kinases, we discovered a series of compounds that block IL-1 beta release produced as a consequence of a stimulus involved in triggering an inflammatory response. The present study reports the hit-to-lead optimization process that permitted the identification of the compound 13b (AIK3-305) an orally available, potent and selective inhibitor of IL-1 beta. Furthermore, the study also reports the results of an in vivo efficacy study of 13b in a LPS endotoxic shock model in male BALB/c mice, where IL-1 beta inhibition is monitored in different tissues. (C) 2021 The Author(s). Published by Elsevier Masson SAS.

Automated summary

A new orally available, potent and selective inhibitor of interleukin-1 beta has been discovered, showing promising results in reducing disease severity and efficacy in a mouse endotoxic shock model.