Development of methyl isoxazoleazepines as inhibitors of BET.

  title={Development of methyl isoxazoleazepines as inhibitors of BET.},
  author={M. Hewitt and Y. Leblanc and Victor S. Gehling and R. Vaswani and A. C{\^o}t{\'e} and Christopher G. Nasveschuk and Alexander M. Taylor and Jean-Christophe Harmange and J. Audia and E. Pardo and Rich Cummings and Shivangi Joshi and P. Sandy and J. Mertz and R. Sims and Louise Bergeron and B. Bryant and S. Bellon and F. Poy and H. Jayaram and Yong Tang and Brian K. Albrecht},
  journal={Bioorganic & medicinal chemistry letters},
  volume={25 9},
  • M. Hewitt, Y. Leblanc, +19 authors Brian K. Albrecht
  • Published 2015
  • Medicine, Chemistry
  • Bioorganic & medicinal chemistry letters
  • In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model. 
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