Search | WHO COVID-19 Research Database

Identification of a novel orally bioavailable NLRP3 inflammasome inhibitor.

Agarwal, Sameer; Pethani, Jignesh P; Shah, Hardik A; Vyas, Vismit; Sasane, Santosh; Bhavsar, Harsh; Bandyopadhyay, Debdutta; Giri, Poonam; Viswanathan, Kasinath; Jain, Mukul R; Sharma, Rajiv.

Bioorg Med Chem Lett ; 30(21): 127571, 2020 11 01.

Article in English | MEDLINE | ID: covidwho-791276

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/pharmacokinetics

ABSTRACT

Subject(s)

SEND TO:

SELECTION OF CITATIONS

SEARCH DETAIL