Strategies to mitigate the bioactivation of 2-anilino-7-aryl-pyrrolo [2, 1-f][1, 2, 4] triazines: identification of orally bioavailable, efficacious ALK inhibitors

…, R Tripathy, JL Diebold, RJ McHugh…

Index: Mesaros, Eugen F.; Thieu, Tho V.; Wells, Gregory J.; Zificsak, Craig A.; Wagner, Jason C.; Breslin, Henry J.; Tripathy, Rabindranath; Diebold, James L.; McHugh, Robert J.; Wohler, Ashley T.; Quail, Matthew R.; Wan, Weihua; Lu, Lihui; Huang, Zeqi; Albom, Mark S.; Angeles, Thelma S.; Wells-Knecht, Kevin J.; Aimone, Lisa D.; Cheng, Mangeng; Ator, Mark A.; Ott, Gregory R.; Dorsey, Bruce D. Journal of Medicinal Chemistry, 2012 , vol. 55, # 1 p. 115 - 125

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Citation Number: 19

Abstract

Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2, 7- disubstituted pyrrolo [2, 1-f][1, 2, 4] triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with ...