title: Allosteric FBPase inhibitors gain 10(5) times in potency when simultaneously binding two neighboring AMP sites.
abstract: Human fructose-1,6-bisphosphatase (FBPase, EC 3.1.3.11) is a key gluconeogenic enzyme, responsible for the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate, and thus presents an opportunity for the development of novel therapeutics focused on lowering the hepatic glucose production in type 2 diabetics. In its active form FBPase exists as a homotetramer and is allosterically regulated by AMP. In an HTS campaign aromatic sulfonylureas have been identified as FBPase inhibitors mimicking AMP. By bridging two adjacent allosteric binding sites using two aromatic sulfonylureas as anchor units and covalently linking them, it was possible to obtain dual binding AMP site inhibitors that exhibit a strong inhibitory effect.
authors.affiliation: F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. paul.hebeisen@roche.com
authors.forename: Paul
authors.initials: P
authors.lastname: Hebeisen
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.forename: Philipp
authors.initials: P
authors.lastname: Kohler
authors.forename: Marcel
authors.initials: M
authors.lastname: Gubler
authors.forename: Walter
authors.initials: W
authors.lastname: Huber
authors.forename: Eric
authors.initials: E
authors.lastname: Kitas
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schott
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.forename: Catherine
authors.initials: C
authors.lastname: Joseph
authors.forename: Armin
authors.initials: A
authors.lastname: Ruf
mesh_terms: D000249:Adenosine Monophosphate / Q000737:chemistry*; D000284:Administration, Oral; D000495:Allosteric Site; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D013453:Sulfonylurea Compounds / Q000737:chemistry
chemical_list: D013453:Sulfonylurea Compounds; D000249:Adenosine Monophosphate; D006597:Fructose-Bisphosphatase; D005947:Glucose