ABSTRACT
In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R2 site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 µg/mL) with low inhibition of CYP 2C9 (IC50 > 10 µM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.
Subject(s)
Antitubercular Agents/pharmacology , Cytochrome P-450 CYP2C9 Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Sulfaphenazole/analogs & derivatives , Sulfaphenazole/pharmacology , Sulfonamides/pharmacology , Antitubercular Agents/chemical synthesis , Cytochrome P-450 CYP2C9 Inhibitors/chemical synthesis , Drug Design , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium tuberculosis/enzymology , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
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
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
