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

…, JK Petkus, EM Doherty, T Nixey, JL Kim…

Index: Smith, Adrian L.; DeMorin, Frenel F.; Paras, Nick A.; Huang, Qi; Petkus, Jeffrey K.; Doherty, Elizabeth M.; Nixey, Thomas; Kim, Joseph L.; Whittington, Douglas A.; Epstein, Linda F.; Lee, Matthew R.; Rose, Mark J.; Babij, Carol; Fernando, Manory; Hess, Kristen; Le, Quynh; Beltran, Pedro; Carnahan, Josette Journal of Medicinal Chemistry, 2009 , vol. 52, # 20 p. 6189 - 6192

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Citation Number: 59

Abstract

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 ...