ABSTRACT
NLRP3 inflammasome mediated release of interleukin-1ß (IL-1ß) has been implicated in various diseases, including COVID-19. In this study, rationally designed alkenyl sulfonylurea derivatives were identified as novel, potent and orally bioavailable NLRP3 inhibitors. Compound 7 was found to be potent (IL-1ß IC50 = 35 nM; IL-18 IC50 = 33 nM) and selective NLRP3 inflammasome inhibitor with excellent pharmacokinetic profile having oral bioavailability of 99% in mice.
Subject(s)
Inflammasomes/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Sulfonylurea Compounds/pharmacology , Administration, Oral , Animals , Betacoronavirus , COVID-19 , Cell Line, Tumor , Coronavirus Infections , Cytochrome P-450 CYP2C8 Inhibitors/administration & dosage , Cytochrome P-450 CYP2C8 Inhibitors/chemical synthesis , Cytochrome P-450 CYP2C8 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP2C8 Inhibitors/pharmacology , Cytochrome P-450 CYP2C9 Inhibitors/administration & dosage , Cytochrome P-450 CYP2C9 Inhibitors/chemical synthesis , Cytochrome P-450 CYP2C9 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP2C9 Inhibitors/pharmacology , Dogs , Drug Stability , Humans , Interleukin-1beta/antagonists & inhibitors , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Molecular Structure , Pandemics , Pneumonia, Viral , Rats , SARS-CoV-2 , Structure-Activity Relationship , Sulfonylurea Compounds/administration & dosage , Sulfonylurea Compounds/chemical synthesis , Sulfonylurea Compounds/pharmacokineticsABSTRACT
NLRP3 inflammasome mediated release of interleukin-1ß (IL-1ß) has been implicated in various diseases. In this study, rationally designed mimics of sulfonylurea moiety were investigated as NLRP3 inhibitors. Our results culminated into discovery of series of unprecedented N-cyano sulfoximineurea derivatives as potent NLRP3 inflammasome inhibitors. Compound 15 (IC50 = 7 nM) and analogues were found to be highly potent and selective NLRP3 inflammasome inhibitor with good pharmacokinetic profile. These effects translate in vivo, as 15, 29, and 34 significantly inhibit NLRP3 dependent IL-1ß secretion in mice.