1579995-07-5Relevant academic research and scientific papers
Discovery of N-Arylsulfonyl-Indole-2-Carboxamide Derivatives as Potent, Selective, and Orally Bioavailable Fructose-1,6-Bisphosphatase Inhibitors - Design, Synthesis, in Vivo Glucose Lowering Effects, and X-ray Crystal Complex Analysis
Zhou, Jie,Bie, Jianbo,Wang, Xiaoyu,Liu, Quan,Li, Rongcui,Chen, Hualong,Hu, Jinping,Cao, Hui,Ji, Wenming,Li, Yan,Liu, Shuainan,Shen, Zhufang,Xu, Bailing
, p. 10307 - 10329 (2020/11/02)
Liver fructose-1,6-bisphosphatase (FBPase) is a key enzyme in the gluconeogenesis pathway. Inhibiting FBPase activity represents a potential treatment for type 2 diabetes mellitus. A series of novel N-arylsulfonyl-4-arylamino-indole-2-carboxamide derivatives have been disclosed as FBPase inhibitors. Through extensive structure-activity relationship investigations, a promising candidate molecule Cpd118 [sodium (7-chloro-4-((3-methoxyphenyl)amino)-1-methyl-1H-indole-2-carbonyl] [(4-methoxyphenyl)sulfonyl)amide] has been identified with high inhibitory activity against human liver FBPase (IC50, 0.029 ± 0.006 μM) and high selectivity relative to the other six AMP-binding enzymes. Importantly, Cpd118 produced significant glucose-lowering effects on both type 2 diabetic KKAy mice and ZDF rats as demonstrated by substantial reductions in the fasting and postprandial blood glucose levels, as well as the HbA1c level. Furthermore, Cpd118 elicited a favorable pharmacokinetic profile with an oral bioavailability of 99.1%. Moreover, the X-ray crystal structure of the Cpd118-FBPase complex was resolved, which revealed a unique binding mode and provided a structural basis for its high potency and selectivity.
Design, synthesis and biological evaluation of 7-nitro-1H-indole-2- carboxylic acid derivatives as allosteric inhibitors of fructose-1,6- bisphosphatase
Bie, Jianbo,Liu, Shuainan,Zhou, Jie,Xu, Bailing,Shen, Zhufang
, p. 1850 - 1862 (2014/03/21)
A series of novel indole derivatives was synthesized as inhibitors of fructose-1,6-bisphosphatase (FBPase). Extensive structure-activity relationships were conducted and led to a potent FBPase inhibitor 3.9 with an IC50 of 0.99 μM. The binding mode of this series of indoles was predicted using CDOCKER algorithm. The results of this research will shed light on the further design and optimization of novel small molecules as FBPase inhibitors.
