Synthesis and in Vitro and in Vivo Evaluation of Phosphoinositide-3-kinase Inhibitors

被引：33

作者：

Burger, Matthew T. ^{[1
]}

Knapp, Mark ^{[1
]}

Wagman, Allan ^{[1
]}

Ni, Zhi-Jie ^{[1
]}

Hendrickson, Thomas ^{[1
]}

Atallah, Gordana ^{[1
]}

Zhang, Yanchen ^{[1
]}

Frazier, Kelly ^{[1
]}

Verhagen, Joelle ^{[1
]}

Pfister, Keith ^{[1
]}

Ng, Simon ^{[1
]}

Smith, Aaron ^{[1
]}

Bartulis, Sarah ^{[1
]}

Merrit, Hanne ^{[1
]}

Weismann, Marion ^{[1
]}

Xin, Xiaohua ^{[1
]}

Haznedar, Joshua ^{[1
]}

Voliva, Charles F. ^{[1
]}

Iwanowicz, Ed ^{[1
]}

Pecchi, Sabina ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Emeryville, CA 94608 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2011年 / 2卷 / 01期

关键词：

phosphoinositide 3-kinase alpha; PI3K/AKT pathway; CANCER; POTENT; IDENTIFICATION; RAPAMYCIN; 3-KINASES; TARGET;

D O I：

10.1021/ml1001932

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. series of 2 morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inhibitors of PI3Ks. Herein, we describe the structure guided optimization of these,pyrimidines with a focus on replacing the phenol moiety, while maintaining potent target inhibition and improving in vivo properties A series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines, which potently inhibit PI3K, were discovered,Within-this series a compound, 17, Was identified with suitable pharmacokinetic (PK) properties, which allowed for the establishment of a PI3K PK/pharmacodynamic-efficacy relationship as determined by in vivo inhibition of AKT(Ser473) phosphorylation and tumor growth inhibition in a mouse A2780 tumor xenograft model.

引用

页码：34 / 38

页数：5

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