title: Sulfonylureido thiazoles as fructose-1,6-bisphosphatase inhibitors for the treatment of type-2 diabetes.
abstract: Sulfonylureido thiazoles were identified from a HTS campaign and optimized through a combination of structure-activity studies, X-ray crystallography and molecular modeling to yield potent inhibitors of fructose-1,6-bisphosphatase. Compound 12 showed favorable ADME properties, for example, F=70%, and a robust 32% glucose reduction in the acute db/db mouse model for Type-2 diabetes.
authors.affiliation: F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. eric_a.kitas@roche.com
authors.forename: Eric
authors.initials: E
authors.lastname: Kitas
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.forename: Paul
authors.initials: P
authors.lastname: Hebeisen
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Wessel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Haap
authors.forename: Armin
authors.initials: A
authors.lastname: Ruf
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.forename: Catherine
authors.initials: C
authors.lastname: Joseph
authors.forename: Walter
authors.initials: W
authors.lastname: Huber
authors.forename: Ruben Alvarez
authors.initials: RA
authors.lastname: Sanchez
authors.forename: Axel
authors.initials: A
authors.lastname: Paehler
authors.forename: Agnes
authors.initials: A
authors.lastname: Benardeau
authors.forename: Marcel
authors.initials: M
authors.lastname: Gubler
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schott
authors.forename: Effie
authors.initials: E
authors.lastname: Tozzo
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D013844:Thiazoles; D006597:Fructose-Bisphosphatase