6LW2

The N-arylsulfonyl-indole-2-carboxamide-based inhibitors against fructose-1,6-bisphosphatase

Summary for 6LW2

• Entry DOI: 10.2210/pdb6lw2/pdb
• Descriptor: Fructose-1,6-bisphosphatase 1, 7-chloranyl-4-[(3-methoxyphenyl)amino]-N-(4-methoxyphenyl)sulfonyl-1-methyl-indole-2-carboxamide (3 entities in total)
• Functional Keywords: fbpase, n-arylsulfonyl-indole-2-carboxamide, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 149549.60

Authors

Wang, X.Y.,Zhou, J.,Xu, B.L. (deposition date: 2020-02-07, release date: 2020-05-13, Last modification date: 2023-11-29)

Primary citation

Zhou, J.,Bie, J.,Wang, X.,Liu, Q.,Li, R.,Chen, H.,Hu, J.,Cao, H.,Ji, W.,Li, Y.,Liu, S.,Shen, Z.,Xu, B.
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.
J.Med.Chem., 63:10307-10329, 2020

PubMed Abstract: 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 -arylsulfonyl-4-arylamino-indole-2-carboxamide derivatives have been disclosed as FBPase inhibitors. Through extensive structure-activity relationship investigations, a promising candidate molecule [sodium (7-chloro-4-((3-methoxyphenyl)amino)-1-methyl-1-indole-2-carbonyl] [(4-methoxyphenyl)sulfonyl)amide] has been identified with high inhibitory activity against human liver FBPase (IC, 0.029 ± 0.006 μM) and high selectivity relative to the other six AMP-binding enzymes. Importantly, 8 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, elicited a favorable pharmacokinetic profile with an oral bioavailability of 99.1%. Moreover, the X-ray crystal structure of the -FBPase complex was resolved, which revealed a unique binding mode and provided a structural basis for its high potency and selectivity.

PubMed: 32820629
DOI: 10.1021/acs.jmedchem.0c00726

Experimental method

X-RAY DIFFRACTION (2.4 Å)