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

Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. adrians@amgen.com

Journal of medicinal chemistry 2009 Oct 22

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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 in xenograft models.

Citation

Adrian L Smith, Frenel F DeMorin, Nick A Paras, Qi Huang, Jeffrey K Petkus, Elizabeth M Doherty, Thomas Nixey, Joseph L Kim, Douglas A Whittington, Linda F Epstein, Matthew R Lee, Mark J Rose, Carol Babij, Manory Fernando, Kristen Hess, Quynh Le, Pedro Beltran, Josette Carnahan. Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. Journal of medicinal chemistry. 2009 Oct 22;52(20):6189-92