Synthesis and structure-activity relationships of 3-phenyl-2-propenamides as inhibitors of glycogen phosphorylase a

A series of 3-phenyl-2-propenamides discovered from a high-throughput screening campaign as novel, potent, glucose-sensitive inhibitors of human liver glycogen phosphorylase a is described. A solid-phase synthesis on DMHB resin was also developed which provided efficient access not only to certain analogues that could not be cleanly made using more traditional means, but also to a variety of additional analogues. The SAR scope and synthetic strategy are presented herein.