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

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 18; pp. 8627 - 8634
• Main Authors: Onda, Kenichi, Shiraki, Ryota, Yonetoku, Yasuhiro, Momose, Kazuhiro, Katayama, Naoko, Orita, Masaya, Yamaguchi, Tomohiko, Ohta, Mitsuaki, Tsukamoto, Shin-ichi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.09.2008; Elsevier
• Subjects: Acrylamides - chemical synthesis; Acrylamides - pharmacology; Binding Sites; Biological and medical sciences; Bis-3-(3,4-dichlorophenyl)acrylamide; Crystallography, X-Ray; Dichlorophen - chemical synthesis; Dichlorophen - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Glycogen phosphorylase; Glycogen Phosphorylase, Liver Form - antagonists & inhibitors; High-throughput screening (HTS); Humans; Hydrophobic and Hydrophilic Interactions; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacology; Medical sciences; Pharmacology. Drug treatments; Solvents - chemistry; Structure-Activity Relationship; Type 2 diabetes; X-ray crystallographic study; Type 2 diabetes; X-ray crystallographic study; High-throughput screening (HTS); Bis-3-(3,4-dichlorophenyl)acrylamide; Glycogen phosphorylase; High throughput screening; Molecular structure; Enzyme; Transferases; Glycosyltransferases; Enzyme inhibitor; Inhibitor enzyme complex; Binding site; X ray diffraction; In vitro; Phosphorylase; Structure activity relation; Chlorine Organic compounds; Hexosyltransferases; Chemical synthesis; Crystalline structure
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.08.010

(2 E,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. 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, (2 E,2′ E)- N, N′-pentane-1,5-diylbis[3-(3,4-dichlorophenyl)acrylamide] ( 6c) inhibited hLGPa with an IC 50 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.