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

• Published in: Journal of medicinal chemistry Vol. 55; no. 1; pp. 115 - 125
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-01-2012
• Subjects: Administration, Oral; Aniline Compounds - chemical synthesis; Aniline Compounds - pharmacokinetics; Aniline Compounds - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological Availability; In Vitro Techniques; Mice; Mice, SCID; Microsomes, Liver - metabolism; Pyrroles - chemical synthesis; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - pharmacokinetics; Triazines - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm2010767

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.