Allosteric inhibitors of Akt1 and Akt2: discovery of [1,2,4]triazolo[3,4-f][1,6]naphthyridines with potent and balanced activity.
A series of [1,2,4]triazolo[3,4-f][1,6]naphthyridine allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been shown to have potent dual Akt1 and 2 cell potency. The representative compound 13 provided potent inhibitory activity against Akt1 and 2 in vivo in a mouse model.
Li
Yiwei
Y
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., 770 Sumneytown Pike, WP14-2, West Point, PA 19486, USA. yiwei_li@merck.com
Liang
Jun
J
Siu
Tony
T
Hu
Essa
E
Rossi
Michael A
MA
Barnett
Stanley F
SF
Defeo-Jones
Deborah
D
Jones
Raymond E
RE
Robinson
Ronald G
RG
Leander
Karen
K
Huber
Hans E
HE
Mittal
Sachin
S
Cosford
Nicholas
N
Prasit
Peppi
P
D000495:Allosteric Site; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008168:Lung / Q000187:drug effects; D051379:Mice; D008956:Models, Chemical; D009287:Naphthyridines / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D009287:Naphthyridines; D014230:Triazoles; D051057:Proto-Oncogene Proteins c-akt