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-flu
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- 作者：Luke Zehnder ; Michael Bennett ; Jerry Meng ; Buwen Huang ; Sacha Ninkovic ; Fen Wang ; John Braganza ; John Tatlock ; Tanya Jewell ; Joe Zhongxiang Zhou ; Ben Burke ; Jeff Wang ; Karen Maegley ; Pramod P. Mehta ; Min-Jean Yin ; Ketan S. Gajiwala ; Michael J. Hickey ; Shinji Yamazaki ; Evan Smith ; Ping Kang ; Anand Sistla ; Elena Dovalsantos ; Michael R. Gehring ; Robert Kania ; Martin Wythes ; Pei-Pei Kung
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：May 12, 2011
- 年：2011
- 卷：54
- 期：9
- 页码：3368-3385
- 全文大小：1443K
- 年卷期：v.54,no.9(May 12, 2011)
- ISSN：1520-4804
文摘
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.