Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline.

  title={Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline.},
  author={Adrian L Smith and Frenel F DeMorin and Nick A Paras and Qi Huang and Jeffrey K Petkus and Elizabeth M. Doherty and Thomas E Nixey and Joseph L Kim and Douglas A. Whittington and Linda F. Epstein and Matthew R Lee and Mark J. Rose and Carol Babij and Manory Fernando and Kristen L Hess and Quynh Le and Pedro Beltr{\'a}n and Josette Carnahan},
  journal={Journal of medicinal chemistry},
  volume={52 20},
The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent… CONTINUE READING

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