N-substituted sultam carboxylic acids as novel glycogen synthase activators

Abstract

Decreased glycogen synthesis and turnover is a common defect in type 2 diabetic patients. Activating glycogen synthase, the enzyme that catalyses the transfer of glucose from UDP-glucose to a glycogen polymer chain, could be a potential therapeutic target for the treatment of diabetes. We discovered a series of N-substituted sultam carboxylic acids as potent glycogen synthase activators. Treatment of human skeletal muscle cells with these compounds resulted in an increase in glycogen synthesis. Compound 4 displayed good oral bioavailability and therefore may be a useful tool molecule to study GS as a potential anti-diabetic target.