Document Report Card

ID: ALA2157957

Journal: J Med Chem

Title: 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.

Authors: Mesaros EF, Thieu TV, Wells GJ, Zificsak CA, Wagner JC, Breslin HJ, Tripathy R, Diebold JL, McHugh RJ, Wohler AT, Quail MR, Wan W, Lu L, Huang Z, Albom MS, Angeles TS, Wells-Knecht KJ, Aimone LD, Cheng M, Ator MA, Ott GR, Dorsey BD.

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 antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.

CiteXplore: 22141319

DOI: 10.1021/jm2010767