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吡唑并嘧啶作为高度有效的、选择性的哺乳动物雷帕霉素靶蛋白(mTOR)的 ATP 竞争性抑制剂：1 位取代基的优化。

Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent.

机构信息

Chemical Sciences, Wyeth Research, 401 N. Middletown Rd, Pearl River, NY 10965, USA.

出版信息

Bioorg Med Chem Lett. 2010 Feb 15;20(4):1440-4. doi: 10.1016/j.bmcl.2009.12.086. Epub 2010 Jan 4.

DOI:10.1016/j.bmcl.2009.12.086
PMID:20089401
Abstract

A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8h following iv administration and showed excellent oral activity in a xenograft tumor model.

摘要

已经制备了一系列具有各种取代基的吡唑并嘧啶类哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，得到了具有优异的活性、选择性和微粒体稳定性的化合物。在 4-位结合环己基缩酮基团和 2,6-亚乙基桥接吗啉，在 6-位结合脲基苯基，得到化合物 8a，它在静脉注射后至少 8 小时体内选择性抑制关键的 mTOR 生物标志物，并在异种移植肿瘤模型中表现出优异的口服活性。

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