Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt

被引：61

作者：

Zhu, Gui-Dong ^{[1
]}

Gong, Jianchun ^{[1
]}

Gandhi, Viraj B. ^{[1
]}

Woods, Keith ^{[1
]}

Luo, Yan ^{[1
]}

Liu, Xuesong ^{[1
]}

Guan, Ran ^{[1
]}

Klinghofer, Vered ^{[1
]}

Johnson, Eric F. ^{[1
]}

Stoll, Vincent S. ^{[1
]}

Marno, Mulugeta ^{[1
]}

Li, Qun ^{[1
]}

Rosenberg, Saul H. ^{[1
]}

Giranda, Vincent L. ^{[1
]}

机构：

[1] Abbott Labs, GPRD, Abbott Pk, IL 60064 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2007年 / 15卷 / 06期

关键词：

protein kinase B; Akt inhibitor; serine/threonine kinase; pyrazolopyridine;

D O I：

10.1016/j.bmc.2007.01.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：2441 / 2452

页数：12

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