Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines.
The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.
Lin
Hong
H
Oncology Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States. hong.2.lin@gsk.com
Yamashita
Dennis S
DS
Xie
Ren
R
Zeng
Jin
J
Wang
Wenyong
W
Leber
Jack
J
Safonov
Igor G
IG
Verma
Sharad
S
Li
Mei
M
Lafrance
Louis
L
Venslavsky
Joseph
J
Takata
Dennis
D
Luengo
Juan I
JI
Kahana
Jason A
JA
Zhang
Shuyun
S
Robell
Kimberly A
KA
Levy
Dana
D
Kumar
Rakesh
R
Choudhry
Anthony E
AE
Schaber
Michael
M
Lai
Zhihong
Z
Brown
Barry S
BS
Donovan
Brian T
BT
Minthorn
Elisabeth A
EA
Brown
Kristin K
KK
Heerding
Dirk A
DA
D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D000882:Haplorhini; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3