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

Paul Hebeisen; Wolfgang Haap; Bernd Kuhn; Peter Mohr; Hans Peter Wessel; Ulrich Zutter; Stephan Kirchner; Armin Ruf; Jörg Benz; Catherine Joseph; Rubén Alvarez-Sánchez; Marcel Gubler; Brigitte Schott; Agnes Benardeau; Effie Tozzo; Eric Kitas

doi:10.1016/j.bmcl.2011.04.044

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

Bioorg Med Chem Lett. 2011 Jun 1;21(11):3237-42. doi: 10.1016/j.bmcl.2011.04.044. Epub 2011 Apr 20.

Authors

Paul Hebeisen¹, Wolfgang Haap, Bernd Kuhn, Peter Mohr, Hans Peter Wessel, Ulrich Zutter, Stephan Kirchner, Armin Ruf, Jörg Benz, Catherine Joseph, Rubén Alvarez-Sánchez, Marcel Gubler, Brigitte Schott, Agnes Benardeau, Effie Tozzo, Eric Kitas

Affiliation

¹ F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland.

PMID: 21550236
DOI: 10.1016/j.bmcl.2011.04.044

Abstract

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.

MeSH terms

Administration, Oral
Allosteric Site
Aminopyridines / chemistry
Aminopyridines / pharmacology*
Animals
Crystallography, X-Ray
Diabetes Mellitus, Type 2
Disease Models, Animal
Enzyme Activation / drug effects*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Fructose-Bisphosphatase / antagonists & inhibitors*
Fructose-Bisphosphatase / chemistry
Fructose-Bisphosphatase / metabolism
Humans
Inhibitory Concentration 50
Liver / enzymology
Mice
Molecular Structure

Substances

Aminopyridines
Enzyme Inhibitors
Fructose-Bisphosphatase