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]pyri

@article{Zehnder2011OptimizationOP,
  title={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]pyri},
  author={Luke Zehnder and M. Nureddin Bennett and Jerry J Meng and Buwen Huang and Sacha Ninkovic and Fen Wang and John F Braganza and John H. Tatlock and Tanya M. Jewell and Joe Zhongxiang Zhou and Ben Burke and Jeff Wang and Karen A. Maegley and Pramod P. Mehta and M Yin and Ketan S. Gajiwala and Michael J. Hickey and Shinji Yamazaki and Evan B Smith and Ping Kang and Anand Sistla and Elena Z Dovalsantos and Michael R Gehring and Robert Kania and Martin J Wythes and Pei-Pei Kung},
  journal={Journal of medicinal chemistry},
  year={2011},
  volume={54 9},
  pages={3368-85}
}
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… CONTINUE READING

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