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triazoles are novel skeletons to inhibit glycogen phosphorylase in the nanomolar range.Best inhibitors of rabbit muscle R = 4-aminophenyl

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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 value of 0.43 μM. Structural studies have revealed the physicochemical diversity of the β-pocket providing information for future rational inhibitor design studies.

A general synthetic method was elaborated for 3,5-disubstituted-1,2,4-triazoles with different groups in positions 3 and 5.