Discovery of Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor CC-223
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- 作者：Deborah S. Mortensen ; Sophie M. Perrin-Ninkovic ; Graziella Shevlin ; Jingjing Zhao ; Garrick Packard ; Sogole Bahmanyar ; Matthew Correa ; Jan Elsner ; Roy Harris ; Branden G. S. Lee ; Patrick Papa ; Jason S. Parnes ; Jennifer R. Riggs ; John Sapienza ; Lida Tehrani ; Brandon Whitefield ; Julius Apuy ; Ren茅 R. Bisonette ; James C. Gamez ; Matt Hickman ; Godrej Khambatta ; Jim Leisten ; Sophie X. Peng ; Samantha J. Richardson ; Brian E. Cathers ; Stacie S. Canan ; Mehran F. Moghaddam ; Heather K. Raymon ; Peter Worland ; Rama Krishna Narla ; Kimberly E. Fultz ; Sabita Sankar
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：July 9, 2015
- 年：2015
- 卷：58
- 期：13
- 页码：5323-5333
- 全文大小：454K
- ISSN：1520-4804
文摘
We report here the synthesis and structure鈥揳ctivity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.