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
A trinuclear copper(II) complex with inositol and 2,2'-bipyridine forms a fibrous hydrogel at pH 12.4, the assembly of discrete trinuclear complex molecules to form the metallogel being assisted by H-bonding and inter- and intramolecular pi-stacking between the bipyridyls.
