New synthesis of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles, nanomolar inhibitors of glycogen phosphorylase

O-Perbenzoylated 5-(β-D-glucopyranosyl)tetrazole was reacted with N-benzyl carboximidoyl chlorides to give the corresponding 4-benzyl-3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles. Removal of the O-benzoyl and N-benzyl protecting groups by base catalysed transesterification and catalytic hydrogenation, respectively, furnished a series of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles with aliphatic, mono- and bicyclic aromatic, and heterocyclic substituents in the 5-position. Enzyme kinetic studies revealed these compounds to inhibit rabbit muscle glycogen phosphorylase b: best inhibitors were the 5-(4-aminophenyl)- (Ki 0.67 μM) and the 5-(2-naphthyl)-substituted (Ki 0.41 μM) derivatives. This study uncovered the C-glucopyranosyl-1,2,4-triazoles as a novel skeleton for nanomolar inhibition of glycogen phosphorylase. [Display omitted] •New synthesis of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles.•Carboximidoylation of O-protected 5-(β-D-glucopyranosyl)tetrazole.•New nanomolar inhibitors of glycogen phosphorylase.