Sulfonylureido thiazoles as fructose-1,6-bisphosphatase inhibitors for the treatment of type-2 diabetes.
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.
Kitas
Eric
E
F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. eric_a.kitas@roche.com
Mohr
Peter
P
Kuhn
Bernd
B
Hebeisen
Paul
P
Wessel
Hans Peter
HP
Haap
Wolfgang
W
Ruf
Armin
A
Benz
Jörg
J
Joseph
Catherine
C
Huber
Walter
W
Sanchez
Ruben Alvarez
RA
Paehler
Axel
A
Benardeau
Agnes
A
Gubler
Marcel
M
Schott
Brigitte
B
Tozzo
Effie
E
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
D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D013844:Thiazoles; D006597:Fructose-Bisphosphatase