Dihydroxyphenylisoindoline Amides as Orally Bioavailable Inhibitors of the Heat Shock Protein 90 (Hsp90) Molecular Chaperone

被引：71

作者：

Kung, Pei-Pei ^{[1
]}

Huang, Buwen ^{[1
]}

Zhang, Gang ^{[1
]}

Zhou, Joe Zhongxiang ^{[1
]}

Wang, Jeff ^{[1
]}

Digits, Jennifer A. ^{[1
]}

Skaptason, Judith ^{[1
]}

Yamazaki, Shinji ^{[1
]}

Neul, David ^{[1
]}

Zientek, Michael ^{[1
]}

Elleraas, Jeff ^{[1
]}

Mehta, Pramod ^{[1
]}

Yin, Min-Jean ^{[1
]}

Hickey, Michael J. ^{[1
]}

Gajiwala, Ketan S. ^{[1
]}

Rodgers, Caroline ^{[1
]}

Davies, Jay F., II ^{[1
]}

Gehring, Michael R. ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, La Jolla Labs, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 01期

关键词：

POTENT ANTITUMOR-ACTIVITY; HEAT-SHOCK-PROTEIN-90; INHIBITORS; CANCER; PHARMACOKINETICS; METABOLISM; CLEARANCE; ASSAY;

D O I：

10.1021/jm901209q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.

引用

页码：499 / 503

页数：5

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