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
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- 作者：Eugen F. Mesaros ; Tho V. Thieu ; Gregory J. Wells ; Craig A. Zificsak ; Jason C. Wagner ; Henry J. Breslin ; Rabindranath Tripathy ; James L. Diebold ; Robert J. McHugh ; Ashley T. Wohler ; Matthew R. Quail ; Weihua Wan ; Lihui Lu ; Zeqi Huang ; Mark S. Albom ; Thelma S. Angeles ; Kevin J. Wells-Knecht ; Lisa D. Aimone ; Mangeng Cheng ; Mark A. Ator ; Gregory R. Ott ; Bruce D. Dorsey
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：January 12, 2012
- 年：2012
- 卷：55
- 期：1
- 页码：115-125
- 全文大小：398K
- 年卷期：v.55,no.1(January 12, 2012)
- ISSN：1520-4804
文摘
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.