Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors

被引：32

作者：

Bencsik, Josef R. ^{[1
]}

Xiao, Dengming ^{[1
]}

Blake, James F. ^{[1
]}

Kallan, Nicholas C. ^{[1
]}

Mitchell, Ian S. ^{[1
]}

Spencer, Keith L. ^{[1
]}

Xu, Rui ^{[1
]}

Gloor, Susan L. ^{[1
]}

Martinson, Matthew ^{[1
]}

Risom, Tyler ^{[1
]}

Woessner, Richard D. ^{[1
]}

Dizon, Faith ^{[1
]}

Wu, Wen-I ^{[1
]}

Vigers, Guy P. A. ^{[1
]}

Brandhuber, Barbara J. ^{[1
]}

Skelton, Nicholas J. ^{[2
]}

Prior, Wei Wei ^{[2
]}

Murray, Lesley J. ^{[2
]}

机构：

[1] Array BioPharma Inc, Boulder, CO 80301 USA

[2] Genentech Inc, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 23期

关键词：

Akt; Kinase; Selectivity; Oral; PKA; THERAPEUTIC TARGET; RECENT PROGRESS; RHO-KINASE; PATHWAY; SURVIVAL; RECEPTOR; CANCER; HEART;

D O I：

10.1016/j.bmcl.2010.09.112

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg. (C) 2010 Elsevier Ltd. All rights reserved.

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收藏

页码：7037 / 7041

页数：5

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