Identification of a novel 3,5-disubstituted pyridine as a potent, selective, and orally active inhibitor of Akt1 kinase.
Based on lead compounds 2 and 3 a series of 3,5-disubstituted pyridines have been designed and evaluated for inhibition of AKT/PKB. Modifications at the 3 position of the pyridine ring led to a number of potent compounds with improved physical properties, resulting in the identification of 11g as a promising, orally active Akt inhibitor. The synthesis, structure-activity relationship studies, and pharmacokinetic data are presented in this paper.
Thomas
Sheela A
SA
Cancer Research, Department R47S, AP10 Abbott Laboratories, 100 Abbott Park Rd, Abbott Park, IL 60064, USA. sheela.thomas@abbott.com
Li
Tongmei
T
Woods
Keith W
KW
Song
Xiaohong
X
Packard
Garrick
G
Fischer
John P
JP
Diebold
Robert B
RB
Liu
Xuesong
X
Shi
Yan
Y
Klinghofer
Vered
V
Johnson
Eric F
EF
Bouska
Jennifer J
JJ
Olson
Amanda
A
Guan
Ran
R
Magnone
Shayna R
SR
Marsh
Kennan
K
Luo
Yan
Y
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
Li
Qun
Q