Optimization of Potent, Selective, and Orally Bioavailable Pyrrolodinopyrimidine-Containing Inhibitors of Heat Shock Protein 90. Identification of Development Candidate 2-Amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo [3,4-d]pyrimidine-6-carboxamide

被引：32

作者：

Zehnder, Luke ^{[1
]}

Bennett, Michael ^{[1
]}

Meng, Jerry ^{[1
]}

Huang, Buwen ^{[1
]}

Ninkovic, Sacha ^{[1
]}

Wang, Fen ^{[1
]}

Braganza, John ^{[1
]}

Tatlock, John ^{[1
]}

Jewell, Tanya ^{[1
]}

Zhou, Joe Zhongxiang ^{[1
]}

Burke, Ben ^{[1
]}

Wang, Jeff ^{[1
]}

Maegley, Karen ^{[1
]}

Mehta, Pramod P. ^{[1
]}

Yin, Min-Jean ^{[1
]}

Gajiwala, Ketan S. ^{[1
]}

Hickey, Michael J. ^{[1
]}

Yamazaki, Shinji ^{[1
]}

Smith, Evan ^{[1
]}

Kang, Ping ^{[1
]}

Sistla, Anand ^{[1
]}

Dovalsantos, Elena ^{[1
]}

Gehring, Michael R. ^{[1
]}

Kania, Robert ^{[1
]}

Wythes, Martin ^{[1
]}

Kung, Pei-Pei ^{[1
]}

机构：

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 09期

关键词：

HEAT-SHOCK-PROTEIN-90; INHIBITORS; HSP90; 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN; DISCOVERY; BINDING;

D O I：

10.1021/jm200128m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.

引用

页码：3368 / 3385

页数：18

共 11 条

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