Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors
Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors
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DOI：
10.1016/j.bmcl.2010.09.112
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发表时间：
2010-12-01
影响因子：
2.7
通讯作者：
Murray, Lesley J.
中科院分区：
文献类型：
--
作者：
Bencsik, Josef R.;Xiao, Dengming;Murray, Lesley J.
在这里，我们报告了发现和合成了一系列新的二氢硫代和二氢呋喃嘧啶（2和3）作为有效的泛Akt抑制剂。利用先前的SAR和对结合位点氨基酸序列的分析，我们设计了抑制剂，与前代吡咯嘧啶相比，抑制剂具有更高的PKA和一般激酶选择性，并且耐受性更好(1)。一种具有代表性的二氢噻吩化合物（34）被推进到PC3-NCI前列腺小鼠肿瘤模型中，当每天口服200 mg/kg时，它显示出剂量依赖性的肿瘤生长和停滞减少。(C) 2010 Elsevier Ltd.版权所有。
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.