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 IC(50) value of 0.023 microM. 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.
Onda
Kenichi
K
Drug Discovery Research, Astellas Pharma Inc., 5-2-3 Toukoudai, Tsukuba, Ibaraki 300-2698, Japan. kenichi.onda@jp.astellas.com
Shiraki
Ryota
R
Yonetoku
Yasuhiro
Y
Momose
Kazuhiro
K
Katayama
Naoko
N
Orita
Masaya
M
Yamaguchi
Tomohiko
T
Ohta
Mitsuaki
M
Tsukamoto
Shin-Ichi
S
D000178:Acrylamides / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004003:Dichlorophen / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D025001:Glycogen Phosphorylase, Liver Form / Q000037:antagonists & inhibitors*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship
D000178:Acrylamides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D012997:Solvents; D025001:Glycogen Phosphorylase, Liver Form; D004003:Dichlorophen