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

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• 作者：Kenichi Onda ; Ryota Shiraki ; Yasuhiro Yonetoku ; Kazuhiro Momose ; Naoko Katayama ; Masaya Orita ; Tomohiko Yamaguchi ; Mitsuaki Ohta ; Shin-ichi Tsukamoto
• 关键词：Glycogen phosphorylase ; X-ray crystallographic study ; Bis-3-(3 ; 4-dichlorophenyl)acrylamide ; Type 2 diabetes ; High-throughput screening (HTS)
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：15 September 2008
• 年：2008
• 卷：16
• 期：18
• 页码：8627-8634
• 全文大小：507 K

文摘

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.