Improvement of the synthesis and pharmacokinetic properties of chromenotriazolopyrimidine MDM2-p53 protein-protein inhibitors

被引：35

作者：

Beck, Hilary P. ^{[1
]}

DeGraffenreid, Michael ^{[1
]}

Fox, Brian ^{[1
]}

Allen, John G. ^{[2
]}

Rew, Yosup ^{[1
]}

Schneider, Stephen ^{[3
]}

Saiki, Anne Y. ^{[4
]}

Yu, Dongyin ^{[4
]}

Oliner, Jonathan D. ^{[4
]}

Salyers, Kevin ^{[5
]}

Ye, Qiuping ^{[6
]}

Olson, Steven ^{[1
]}

机构：

[1] Amgen Inc, Chem Res & Discovery, San Francisco, CA 94080 USA

[2] Amgen Inc, Chem Res & Discovery, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Chem Res & Discovery, Cambridge, MA 02142 USA

[4] Amgen Inc, Oncol Res, Thousand Oaks, CA 91320 USA

[5] Amgen Inc, PKDM, Thousand Oaks, CA 91320 USA

[6] Amgen Inc, PKDM, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 09期

关键词：

Oncology; Protein-protein interaction; Pharmacokinetics; SMALL-MOLECULE INHIBITORS; CANCER-THERAPY; P53; AMPLIFICATION; APOPTOSIS; STABILITY; BINDING;

D O I：

10.1016/j.bmcl.2010.11.027

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Human murine double minute 2 (MDM2) is a negative regulator of p53, which plays an important role in cell cycle and apoptosis. We report several optimizations to the synthesis of the chromenotriazolopyrimidine series of MDM2-p53 protein-protein interaction inhibitors. Additionally, the in vitro and in vivo stability, pharmacokinetic properties and solubility were improved through N-substitution. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2752 / 2755

页数：4

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