Inhibition of Glycogen Phosphorylase in the Context of Type 2 Diabetes, with Focus on Recent Inhibitors Bound at the Active Site

J.-P.      Praly; S.      Vidal

Abstract

Among the variety of approaches for pharmacological intervention in T2DM, the inhibition of GP with the aim of reducing hepatic glucose output is a validated and thoroughly investigated strategy. Both the academia and health companies participate in the search of potent inhibitors, that might be suitable for long-term treatment. As several inhibitory sites have been identified for GP, interest focuses mainly on structures that can bind at either the catalytic, the allosteric, or the new allosteric sites. Glucose-based motifs and azasugars that bind at the active site constitute the most populated class of GPis. During the last two years, significant progresses have been made, since newly proposed motifs have Ki values in the low micromolar and even sub- micromolar range. Without ignoring previously reported structures, new series based on β-D-glucopyranosyl-pyrimidine, D-glucopyranosylidene-spiro-isoxazoline and D-glucopyranosylidene-spirooxathiazole motifs appear promising. A representative from this last series, with a 2-naphthyl residue was identified as the most potent GPi to date (Ki = 0.16 μM). While no inhibition was found for sulfonium analogs, D-DAB remains the best inhibitor among five and six-membered iminosugars that showed inhibitory properties toward GP. A study of glucagoninduced glucose production in primary rat hepatocytes has suggested that amylo-1,6-glucosidase inhibitors in combination with GPis may lower glucose level in T2DM. Considering the limitations found for other potent GPis binding at other sites and the complexity of pharmacological development, the potential of glucose-based GPis is still not established firmly and more tests with cells, tissues, animals are required to better establish the risks and merits of these structures, as antidiabetic drugs. Further studies might also confirm other directions where glucose-based GPis could be useful.

Keywords: Diabetes, enzymology, glucose-based inhibitors, glycogen phosphorylase, glycomimics, hyperglycemia, inhibitors, type 2 diabetes mellitus, azasugars, D-glucopyranosyl-pyrimidine, D-glucopyranosylidene-spiro-isoxazoline, D-glucopyranosylidene-spiro-oxathiazole, 2-naphthyl residue, sulfonium analogs, iminosugars, amylo-1,6-glucosidase inhibitors, antidiabetic drugs, insulin producing -cells, insulin defi-ciency, non-insulin dependent diabetes mellitus, biguanides, sulfonylureas, thiazolidinediones, glucosidase inhibitors, blood glucose levels, cerebral ventricle, glucose metabolism, adipokines, Peroxisome proliferator, –, activated receptor, thiazolidinedi-ones, pancreatic hormones, insulin, glucagon, metabolic syndrome, peroxisome proliferator-activated receptor, C-aryl glycosides, Hepatic Glucose Production, -1,4-glycosidic bond, hepatic gluconeogenesis pathway, endogenous glucose production, metabolic clearance rate, Impaired Glucose Tolerance, glucokinase, glycogen phos-phorylase inhibitors, GP Isoforms, GP isozymes, acute myocardial infarction, ischaemic myocardial damage, BGP expression, adenoma-carcinoma, de novo colorectal carcinoma, human GP homodimers, Phe285, Tyr613, glucose oligomers, cyclodextrines, 1,4-glycosidic bond, heptenitol 3, maltodextrin phosphorylase, D-glucopyranosyl ring, Caffeine, Ser14 site, GS activation, D-DAB 13, glycogen synthase, glycogen-associated protein phosphatase-1, phosphorylase kinase, spiro-hydantoins, X-ray crystallography, C-D-Glucopyranosyl Type, D-xylose, cellobiose, GP inhibitor, hyperglycaemia, (-D-Glucopyranosyl)cyclopropylamine, Glucosides, C-D-Glucopyranosyl hydro(benzo)quinones, S-D-Glucopyranosides, S-D-glucopyranosyl sulfonamide, O-, S-, and N-Glycosides of hept-2-ulosopyranosonamides, hydrophilic sugar moieties, glucopyranosyl ring, N-D-Glucopyranosyl pyrimidines, N-D-Glucopyranosylamides, C-D-Glucopyranosyl-oxadiazole, 1-(-D-glucopyranosyl)-1,2,3-triazole Derivatives, N--D-Glucopyranosyl(acyl)ureas and biurets, Deoxy-3-fluoro-D-glucopyranosyl-pyrimidine derivatives, C-D-Glucopyranosylated oxadiazoles, 1-(-D-Glucopyranosyl)-1,2,3-triazoles, Triazoles, spiro-1,4,2-oxathiazole Derivatives, D-Glucopyranosylidene-spiro-1,4,2-oxathiazoles