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

作者：Kun Sandor; Bokor Eva; Varga Gergely; Szocs Bela; Pahl Andras; Czifrak Katalin; Toth Marietta; Juhasz Laszlo; Docsa Tibor; Gergely Pal; Somsak Laszlo^*

来源：European Journal of Medicinal Chemistry, 2014, 76: 567-579.

DOI：10.1016/j.ejmech.2014.02.041

• 1,2,4-Triazole
• C-glucopyranosyl derivative
• Bioisoster
• Glycogen phosphorylase
• Inhibitor

O-Perbenzoylated 5-(beta-D-glucopyranosyl)tetrazole was reacted with N-benzyl carboximidoyl chlorides to give the corresponding 4-benzyl-3-(beta-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-(beta-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)- (K-i 0.67 mu M) and the 5-(2-naphthyl)-substituted (K-i 0.41 mu M) derivatives. This study uncovered the C-glucopyranosyl-1,2,4-triazoles as a novel skeleton for nanomolar inhibition of glycogen phosphorylase.

• 出版日期2014-4-9