The NLRP3 inflammasome is a multiprotein complex that
facilitates
activation and release of the proinflammatory cytokines interleukin-1β
(IL-1β) 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.