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.
ABSTRACT
TGR5 is a member of G protein-coupled receptor (GPCR) superfamily, a promising molecular target for metabolic diseases. Activation of TGR5 promotes secretion of glucagon-like peptide-1 (GLP-1), which activates insulin secretion. A series of 2-thio-imidazole derivatives have been identified as novel, potent and orally efficacious TGR5 agonists. Compound 4d, a novel TGR5 agonist, in combination with Sitagliptin, a DPP-4 inhibitor, has demonstrated an adequate GLP-1 secretion and glucose lowering effect in animal models, suggesting a potential clinical option in treatment of type-2 diabetes.
Subject(s)
Hypoglycemic Agents/chemistry , Imidazoles/chemistry , Receptors, G-Protein-Coupled/agonists , Animals , Binding Sites , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/veterinary , Drug Therapy, Combination , Female , Glucagon-Like Peptide 1/metabolism , Half-Life , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Imidazoles/pharmacokinetics , Imidazoles/therapeutic use , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Protein Structure, Tertiary , Receptors, G-Protein-Coupled/metabolism , Sitagliptin Phosphate/therapeutic use , Structure-Activity RelationshipABSTRACT
GPR40/FFAR1 is a G protein-coupled receptor predominantly expressed in pancreatic ß-cells and activated by long-chain free fatty acids, mediating enhancement of glucose-stimulated insulin secretion. A novel series of substituted 3-(4-aryloxyaryl)propanoic acid derivatives were prepared and evaluated for their activities as GPR40 agonists, leading to the identification of compound 5, which is highly potent in in vitro assays and exhibits robust glucose lowering effects during an oral glucose tolerance test in nSTZ Wistar rat model of diabetes (ED50 = 0.8 mg/kg; ED90 = 3.1 mg/kg) with excellent pharmacokinetic profile, and devoid of cytochromes P450 isoform inhibitory activity.
ABSTRACT
TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED50 of 7.9 mg/kg and ED90 of 29.2 mg/kg.
