Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity.
The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse i.v. t(1/2) = 0.3 h, p.o. F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (i.v. t(1/2) = 5.0 h, p.o. F = 51%) but resulted in >500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity.
Zhu
Gui-Dong
GD
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. gui-dong.zhu@abbott.com
Gong
Jianchun
J
Claiborne
Akiyo
A
Woods
Keith W
KW
Gandhi
Viraj B
VB
Thomas
Sheela
S
Luo
Yan
Y
Liu
Xuesong
X
Shi
Yan
Y
Guan
Ran
R
Magnone
Shayna R
SR
Klinghofer
Vered
V
Johnson
Eric F
EF
Bouska
Jennifer
J
Shoemaker
Alexander
A
Oleksijew
Anatol
A
Stoll
Vincent S
VS
De Jong
Ron
R
Oltersdorf
Tilman
T
Li
Qun
Q
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt; C039109:isoquinoline; C023666:pyridine