Structure-activity relationships of 3,5-disubstituted benzamides as glucokinase activators with potent in vivo efficacy

The optimization of our lead GK activator 2a to 3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl) phenoxy]-N-1,3-thiazol-2-ylbenzamide (6g), a potent GK activator with good oral availability, is described, including to uncouple the relationship between potency and hydrophobicity. Following oral administration, this compound exhibited robust glucose lowering in diabetic model rodents. (C) 2009 Elsevier Ltd. All rights reserved.