Synthesis of N-glucopyranosidic derivatives as potential inhibitors that bind at the catalytic site of glycogen phosphorylase.
Glycogen phosphorylase (GP) is a promising molecular target for the treatment of Type 2 diabetes. The design of potential inhibitors for the catalytic site of the enzyme is based on the high affinity for β-D-glucopyranose and the presence of a β-cavity that extends from the sugar anomeric position forming a 15 x 7.5 x 10 Å available space. This review is focused on our efforts towards the design and synthesis of various families of potential inhibitors, including N-β-D-glucopyranosyl oxamic acid esters and oxamides, N-β-D-glucopyranosylaminocarbonyl L-aminoacids and peptides, as well as glucose-derived purine and pyrimidine nucleosides, spiro- and other bicyclic derivatives. Kinetic and crystallographic study of the interactions of these inhibitors with GP has increased our understanding of the importance of the various functional groups within the catalytic site and has pointed the way towards the in silico prediction and design of potent inhibitors, which are both synthetically viable and pharmacologically relevant.
Gimisis
Thanasis
T
Organic Chemistry Laboratory, Department of Chemistry, School of Sciences, National and Kapodistrian University of Athens, 15771 Panepistimiopolis, Athens, Greece. gimisis@chem.uoa.gr
D020134:Catalytic Domain; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010072:Oxamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D009705:Nucleosides; D010455:Peptides; D013141:Spiro Compounds; D024981:Glycogen Phosphorylase; D005947:Glucose; D010072:Oxamic Acid; C008728:oxamide