2,7-Disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New Variant of an Old Template and Application to the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors with in Vivo Antitumor Activity
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- 作者：Gregory R. Ott ; Gregory J. Wells ; Tho V. Thieu ; Matthew R. Quail ; Joseph G. Lisko ; Eugen F. Mesaros ; Diane E. Gingrich ; Arup K. Ghose ; Weihua Wan ; Lihui Lu ; Mangeng Cheng ; Mark S. Albom ; Thelma S. Angeles ; Zeqi Huang ; Lisa D. Aimone ; Mark A. Ator ; Bruce A. Ruggeri ; Bruce D. Dorsey
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：September 22, 2011
- 年：2011
- 卷：54
- 期：18
- 页码：6328-6341
- 全文大小：1178K
- 年卷期：v.54,no.18(September 22, 2011)
- ISSN：1520-4804
文摘
A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.