ABSTRACT
O-glucuronides and O-glucosides of a series of pyrazoles analogues were synthesized and evaluated for their SGLT inhibitory activity in brush border membrane vehicles (BBMVs) of rat kidney. O-glucosides of certain pyrazole analogues inhibited the transport of [(14)C]-glucose in BBMVs, and induced glucosuria in Wistar rats by intravenous injection.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glucosides/chemical synthesis , Glucosides/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Kidney/metabolism , Membrane Glycoproteins/antagonists & inhibitors , Monosaccharide Transport Proteins/antagonists & inhibitors , Animals , Enzyme Inhibitors/administration & dosage , Glucose/metabolism , Glucosides/administration & dosage , Glycosuria/chemically induced , Glycosuria/metabolism , Hypoglycemic Agents/administration & dosage , Indicators and Reagents , Injections, Intravenous , Kidney/drug effects , Microvilli/drug effects , Microvilli/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Rats , Rats, Wistar , Sodium-Glucose Transporter 1 , Structure-Activity RelationshipABSTRACT
Endothelial cells participate in the inflammatory and immune reactions. Endothelial cell activation is a recurrent phenomenon linked to the pathogenesis of diverse human diseases, such as acute and chronic inflammation and cardiovascular disorders. Pro-inflammatory cytokines (e.g., IL-1, TNF) are well-known activators of endothelial cells, since they strongly induce production of chemokines (e.g., IL-8, MCP-1) and cell adhesion molecules, resulting in an activation of inflammatory transcription factors such as NF-kappaB. We have established a cell-based reporter assay for the NF-kappaB-dependent gene activation in HUVEC. Using this assay system, we have identified a novel synthetic small molecule, APC0576, 5-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)-2-(4-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)phenoxy)pyridine, as an inhibitor of IL-1-induced NF-kappaB-dependent gene activation without any adverse effects on the cell viability. APC0576 represses the IL-1-induced release of chemokines (e.g., IL-8, MCP-1) in HUVEC. This inhibitory effect occurred at the level of mRNA expression. Despite having a strong inhibitory effect on the NF-kappaB-dependent transcriptional activation, APC0576 does not inhibit the IL-1-induced DNA binding of NF-kappaB, degradation of I-kappaB-alpha, or phosphorylation of RelA (p65). Although its molecular mechanism of action is not yet clear, APC0576 is a promising therapeutic candidate for diverse diseases involved in the pathogenic endothelial activation.
