Glycogen phosphorylase inhibitors: a patent review (2013-2015)

Introduction: Control of glycemia is crucial in the treatment of type 2 diabetes complications. Glycogen phosphorylase (GP) releases glucose from the liver into the blood stream. Design of potent GP inhibitors is a therapeutic strategy in the context of type 2 diabetes. Areas covered: Glucose-based inhibitors have found potential applications since they now reach low nanomolar K-i values. Another set of patents disclose cholic acid/7-aza-indole conjugates for targeted drug delivery to the liver. A series of benzazepinones have also been reported as potent GP inhibitors. In vitro data are reported for GP inhibition but the in vivo biological data at the cellular or animal levels are often missing, even though the literature reported for these molecules is also discussed. Expert opinion: A structural analogy between glucose-based GP inhibitors and C-glucosides targeting sodium glucose co-transporter 2 (SGLT2) is intriguing. Cholic acid/7-aza-indole conjugates are promising in vivo drug delivery systems to the liver. Benzazepinones were very recently described and no associated literature is available, making it very difficult to comment at present. While industry has slowed down on GP inhibitors design, academic groups are pursuing investigations and have provided potential drug candidates which will resuscitate the interest for GP, including its potential for targeting cancer.