Optimization of Potent, Selective, and Orally Bioavailable Pyrrolodinopyrimidine-Containing Inhibitors of Heat Shock Protein 90. Identification of Development …

L Zehnder, M Bennett, J Meng, B Huang…

Index: Zehnder, Luke; Bennett, Michael; Meng, Jerry; Huang, Buwen; Ninkovic, Sacha; Wang, Fen; Braganza, John; Tatlock, John; Jewell, Tanya; Zhou, Joe Zhongxiang; Burke, Ben; Wang, Jeff; Maegley, Karen; Mehta, Pramod P.; Yin, Min-Jean; Gajiwala, Ketan S.; Hickey, Michael J.; Yamazaki, Shinji; Smith, Evan; Kang, Ping; Sistla, Anand; Dovalsantos, Elena; Gehring, Michael R.; Kania, Robert; Wythes, Martin; Kung, Pei-Pei Journal of Medicinal Chemistry, 2011 , vol. 54, # 9 p. 3368 - 3385

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Citation Number: 21

Abstract

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 ...