620596-72-7Relevant articles and documents
Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase
Zhang, Lei,Chen, Xiaojie,Liu, Jun,Zhu, Qingzhang,Leng, Ying,Luo, Xiaomin,Jiang, Hualiang,Liu, Hong
, p. 624 - 639 (2013/02/21)
Dual-target-directed agents simultaneously inhibiting glycogen phosphorylase (GP) and activating glucokinase (GK) could decelerate the inflow of glucose from glycogenolysis and accelerate the outflow of glucose in the liver, therefore allow for a better control over hyperglycaemia in a synergetic manner. A series of hybrid compounds were designed by structure-assisted and ligand-based strategies. In vitro bioassays found two novel compounds (1j, 6g) worthy of further optimization on balance of dual action to GP and GK. In addition, for single-target activity, two compounds exhibited more potent GP inhibitory activity and four compounds showed better GK activation than their corresponding references.
Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives as inhibitors of human liver glycogen phosphorylase a
Onda, Kenichi,Suzuki, Takayuki,Shiraki, Ryota,Yonetoku, Yasuhiro,Negoro, Kenji,Momose, Kazuhiro,Katayama, Naoko,Orita, Masaya,Yamaguchi, Tomohiko,Ohta, Mitsuaki,Tsukamoto, Shin-ichi
, p. 5452 - 5464 (2008/12/21)
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 IC50 of 0.90 μM. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC50 of 0.62 μM 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.
