Amino acid anthranilamide derivatives as a new class of glycogen phosphorylase inhibitors.
A series of amino acid anthranilamide derivatives identified from a high-throughput screening campaign as novel, potent, and glucose-sensitive inhibitors of human liver glycogen phosphorylase a are described. A solid-phase synthesis using Wang resin was also developed which provided efficient access to a variety of analogues, and resulted in the identification of key structure-activity relationships, and the discovery of a potent exemplar (IC(50)=80 nM). The SAR scope, synthetic strategy, and in vitro results for this series are presented herein.
Evans
Karen A
KA
Discovery Research, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA. karen.a.evans@gsk.com
Li
Yue H
YH
Coppo
Frank T
FT
Graybill
Todd L
TL
Cichy-Knight
Maria
M
Patel
Mehul
M
Gale
Jennifer
J
Li
Hu
H
Thrall
Sara H
SH
Tew
David
D
Tavares
Francis
F
Thomson
Stephen A
SA
Weiel
James E
JE
Boucheron
Joyce A
JA
Clancy
Daphne C
DC
Epperly
Andrea H
AH
Golden
Pamela L
PL
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D025001:Glycogen Phosphorylase, Liver Form / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D008956:Models, Chemical; D051381:Rats; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology
D000596:Amino Acids; D062367:ortho-Aminobenzoates; D014508:Urea; D025001:Glycogen Phosphorylase, Liver Form; C000219:anthranilamide