- 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
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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.
- 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
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supporting information
p. 10307 - 10329
(2020/11/02)
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- N-acyl sulfamide FBPase inhibitor, preparation method thereof, drug composition and application
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The invention discloses an N-acryl sulfamide FBPase inhibitor of a novel structure, and a preparation method thereof, a drug composition and an application, and particularly relates to an N-acryl sulfamide FBPase inhibitor shown in the formula I, a salt thereof for medicine, a preparation method, a composition comprising one or more compounds, an application of the compound in preparing the FBPase inhibitor or a drug for treating FBPase-related diseases, and an application in preparing a drug for preventing and/or treating diabetes. The formula is shown in the description.
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Paragraph 2380; 2388; 2389
(2017/09/08)
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