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.
Li
Yue H
YH
Discovery Research, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA.
Coppo
Frank T
FT
Evans
Karen A
KA
Graybill
Todd L
TL
Patel
Mehul
M
Gale
Jennifer
J
Li
Hu
H
Tavares
Francis
F
Thomson
Stephen A
SA
D000178:Acrylamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D006801:Humans; D008099:Liver / Q000201:enzymology; D012117:Resins, Synthetic / Q000737:chemistry; D013329:Structure-Activity Relationship
D000178:Acrylamides; D004791:Enzyme Inhibitors; D012117:Resins, Synthetic; D024981:Glycogen Phosphorylase