Synthesis and pharmacological evaluation of bis-3-(3,4-dichlorophenyl)acrylamide derivatives as glycogen phosphorylase inhibitors

During our research using a high-throughput screening system for discovery of a new class of human liver glycogen phosphorylase a (hLGPa) inhibitors, a series of 3-(3,4-dichlorophenyl)acrylamide derivatives were synthesized, and their inhibitory activities toward hLGPa were evaluated. Among the derivatives, (2E,2′E)-N,N′-pentane-1,5-diylbis[3-(3,4-dichlorophenyl)acrylamide] (6c) inhibited hLGPa with an IC50 value of 0.023 μM. An X-ray crystallographic study of the enzyme–6c complex showed that the inhibitor is bound at the dimer interface site, where the 3,4-dichlorophenyl moiety interacts hydrophobically with the enzyme.

(2E,2′E)-N,N′-Pentane-1,5-diylbis[3-(3,4-dichlorophenyl)acrylamide] and its heteroatom-containing analogues are potent inhibitors of human liver glycogen phosphorylase a (hLGPa), which binds in the solvent cavity at the hLGPa dimer interface.Figure optionsDownload as PowerPoint slide