Sulfonylureido thiazoles as fructose-1,6-bisphosphatase inhibitors for the treatment of Type-2 diabetes

Sulfonylureido thiazole 12, a potent inhibitor of fructose-1,6-bisphosphatase 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. 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.