The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer
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- 作者：Richard T. Lewis ; Christiane M. Bode ; Deborah M. Choquette ; Michele Potashman ; Karina Romero ; John C. Stellwagen ; Yohannes Teffera ; Earl Moore ; Douglas A. Whittington ; Hao Chen ; Linda F. Epstein ; Renee Emkey ; Paul S. Andrews ; Violeta L. Yu ; Douglas C. Saffran ; Man Xu ; Allison Drew ; Patricia Merkel ; Steven Szilvassy ; Rachael L. Brake
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：July 26, 2012
- 年：2012
- 卷：55
- 期：14
- 页码：6523-6540
- 全文大小：589K
- 年卷期：v.55,no.14(July 26, 2012)
- ISSN：1520-4804
文摘
A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure鈥揳ctivity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound 49 achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds 36 and 49 show favorable potency and PK characteristics in preclinical species indicative of suitability for further development.