Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives as inhibitors of human liver glycogen phosphorylase a

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• 作者：Kenichi Onda ; Takayuki Suzuki ; Ryota Shiraki ; Yasuhiro Yonetoku ; Kenji Negoro ; Kazuhiro Momose ; Naoko Katayama ; Masaya Orita ; Tomohiko Yamaguchi ; Mitsuaki Ohta ; Shin-ichi Tsukamoto
• 关键词：Glycogen phosphorylase ; Hepatic glucose output ; Diabetes ; Crystallographic determination
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 May 2008
• 卷：16
• 期：10
• 页码：5452-5464
• 文件大小：567 K

摘要

A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl)phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an ICb>50b> of 0.90 bc;M. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an ICb>50b> of 0.62 bc;M and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa.