Array BioPharma Inc., Boulder, CO 80301, USA.
Bioorg Med Chem Lett. 2010 Dec 1;20(23):7037-41. doi: 10.1016/j.bmcl.2010.09.112. Epub 2010 Sep 29.
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.
在此，我们报告了一系列新型二氢噻吩并和二氢呋喃并嘧啶（2 和 3）的发现和合成，它们是有效的全 Akt 抑制剂。利用之前在结合位点的氨基酸序列的 SAR 和分析，我们设计出的抑制剂与前体吡咯并嘧啶（1）相比，显示出更高的 PKA 和一般激酶选择性，并且具有更好的耐受性。一种代表性的二氢噻吩化合物（34）在 PC3-NCI 前列腺小鼠肿瘤模型中得到了进一步研究，当每天口服 200mg/kg 时，它表现出剂量依赖性的肿瘤生长减少和停滞。
