Probing the beta-pocket of the active site of human liver glycogen phosphorylase with 3-(C-beta-d-glucopyranosyl)-5-(4-substituted-phenyl)-1, 2, 4-triazole inhibitors.

Abstract Human liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a β -1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the β -pocket. Recently, C- β - d -glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP. Here we probe the β -pocket by studying the inhibitory effect of six different groups at the para position of 3-( β - d -glucopyranosyl phenyl)-5-phenyl-, 1, 2, 4-triazoles in hlGP by kinetics and X-ray crystallography. The most bioactive compound was the one with an amine substituent to show a K i value of 0.43 μM. Structural studies have revealed the physicochemical diversity of the β -pocket providing information for future rational inhibitor design studies.