Orally active aminopyridines as inhibitors of tetrameric fructose-1,6-bisphosphatase

Compound 19 is representative of a novel sulfonylureido pyridine series that yielded potent inhibitors of fructose-1,6-bisphosphatase, showing significant glucose reduction and modest glycogen lowering in the acute db/db mouse model for Type-2 diabetes. A novel sulfonylureido pyridine series exempli...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (11), p.3237-3242
Main Authors: Hebeisen, Paul, Haap, Wolfgang, Kuhn, Bernd, Mohr, Peter, Wessel, Hans Peter, Zutter, Ulrich, Kirchner, Stephan, Ruf, Armin, Benz, Jörg, Joseph, Catherine, Alvarez-Sánchez, Rubén, Gubler, Marcel, Schott, Brigitte, Benardeau, Agnes, Tozzo, Effie, Kitas, Eric
Format: Article
Language:English
Subjects:
Administration, Oral
Allosteric inhibition
Allosteric Site
Aminopyridines - chemistry
Aminopyridines - pharmacology
animal models
Animals
binding sites
Biological and medical sciences
Crystallography, X-Ray
db/db Mouse model
Diabetes Mellitus, Type 2
Disease Models, Animal
Enzyme Activation - drug effects
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
FBPase
Fructose-1,6-bisphosphatase
Fructose-Bisphosphatase - antagonists & inhibitors
Fructose-Bisphosphatase - chemistry
Fructose-Bisphosphatase - metabolism
General and cellular metabolism. Vitamins
Genotoxicity
glucose
Glucose reduction
glycogen
Humans
Inhibitory Concentration 50
Liver - enzymology
Medical sciences
Mice
Molecular Structure
noninsulin-dependent diabetes mellitus
Pharmacology. Drug treatments
pyridines
Structure–activity studies
X-ray crystallography
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Summary:Compound 19 is representative of a novel sulfonylureido pyridine series that yielded potent inhibitors of fructose-1,6-bisphosphatase, showing significant glucose reduction and modest glycogen lowering in the acute db/db mouse model for Type-2 diabetes. A novel sulfonylureido pyridine series exemplified by compound 19 yielded potent inhibitors of FBPase showing significant glucose reduction and modest glycogen lowering in the acute db/db mouse model for Type-2 diabetes. Our inhibitors occupy the allosteric binding site and also extend into the dyad interface region of tetrameric FBPase.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.04.044