Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity

被引：37
|
作者：
Zhu, GD [1 ]
Gong, JC
Claiborne, A
Woods, KW
Gandhi, VB
Thomas, S
Luo, Y
Liu, XS
Shi, Y
Guan, R
Magnone, SR
Klinghofer, V
Johnson, EF
Bouska, J
Shoemaker, A
Oleksijew, A
Stoll, VS
De Jong, R
Oltersdorf, T
Li, Q
Rosenberg, SH
Giranda, VL
机构：
[1] Abbott Labs, GPRD, Abbott Pk, IL 60064 USA
[2] IDUN Pharmaceut Inc, San Diego, CA 92121 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 12期
关键词：
Akt inhibitor; protein kinase B; PKB; GSK3; FL5.12-Akt; anticancer;
D O I：
10.1016/j.bmcl.2006.03.041
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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 iv t(1/2) = 0.3 h, po F= 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t(1/2) = 5.0 h, po 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. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码：3150 / 3155
页数：6
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