| Literature DB >> 26083478 |
Deborah S Mortensen1, Sophie M Perrin-Ninkovic1, Graziella Shevlin1, Jingjing Zhao1, Garrick Packard1, Sogole Bahmanyar1, Matthew Correa1, Jan Elsner1, Roy Harris1, Branden G S Lee1, Patrick Papa1, Jason S Parnes1, Jennifer R Riggs1, John Sapienza1, Lida Tehrani1, Brandon Whitefield1, Julius Apuy1, René R Bisonette1, James C Gamez1, Matt Hickman1, Godrej Khambatta1, Jim Leisten1, Sophie X Peng1, Samantha J Richardson1, Brian E Cathers1, Stacie S Canan1, Mehran F Moghaddam1, Heather K Raymon1, Peter Worland1, Rama Krishna Narla1, Kimberly E Fultz1, Sabita Sankar1.
Abstract
We report here the synthesis and structure-activity 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.Entities:
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Year: 2015 PMID： 26083478 DOI： 10.1021/acs.jmedchem.5b00626
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446