ABSTRACT
Design, synthesis and biological evaluation of the imidazopyridine analogs as novel GSK3ß inhibitors for treatment of type 2 diabetes mellitus are described. Most of the analogs exhibited excellent inhibitory activities (IC50<44 nM) against glycogen synthase kinase 3ß (GSK3ß). The structure-activity relationship (SAR) of the imidazopyridine analogs and the binding mode of analog 23 in the catalytic domain of GSK3ß, based on our X-ray crystallography study, are described. In particular, analog 28, which was selected as a potential drug candidate for treatment of type 2 diabetes mellitus, exhibited excellent GSK3ß inhibition, pharmacokinetic profiles and blood glucose lowering effect in mouse.
Subject(s)
Aminopyridines/chemical synthesis , Drug Design , Hypoglycemic Agents/chemical synthesis , Imidazoles/chemistry , Imidazoles/chemical synthesis , Pyridines/chemistry , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/therapeutic use , Animals , Binding Sites , Blood Glucose/analysis , Crystallography, X-Ray , Diabetes Mellitus, Experimental/drug therapy , Glycogen Synthase Kinase 3/metabolism , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Imidazoles/pharmacokinetics , Imidazoles/therapeutic use , Male , Mice , Mice, Inbred ICR , Microsomes/metabolism , Protein Structure, Tertiary , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Structure-Activity RelationshipABSTRACT
A highly effective protocol for palladium-catalyzed selective arylation and heteroarylation of indolizines at C-3 has been developed. Mechanistic studies unambiguously support an electrophilic substitution pathway for this transformation.
