2,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles.
A novel series of AKT inhibitors containing 2,3,5-trisubstituted pyridines with novel azaindazoles as hinge binding elements are described. Among these, the 4,7-diazaindazole compound 2c has improved drug-like properties and kinase selectivity than those of indazole 1, and displays greater than 80% inhibition of GSK3beta phosphorylation 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
Zeng
Jin
J
Xie
Ren
R
Verma
Sharad
S
Luengo
Juan I
JI
Rhodes
Nelson
N
Zhang
Shuyun
S
Robell
Kimberly A
KA
Choudhry
Anthony E
AE
Lai
Zhihong
Z
Kumar
Rakesh
R
Minthorn
Elisabeth A
EA
Brown
Kristin K
KK
Heerding
Dirk A
DA
D000818:Animals; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3