jm5b00627_si_002.csv (3.52 kB)

Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115

Download (3.52 kB)
posted on 23.07.2015, 00:00 by Deborah S. Mortensen, Sophie M. Perrin-Ninkovic, Graziella Shevlin, Jan Elsner, Jingjing Zhao, Brandon Whitefield, Lida Tehrani, John Sapienza, Jennifer R. Riggs, Jason S. Parnes, Patrick Papa, Garrick Packard, Branden G.S. Lee, Roy Harris, Matthew Correa, Sogole Bahmanyar, Samantha J. Richardson, Sophie X. Peng, Jim Leisten, Godrej Khambatta, Matt Hickman, James C. Gamez, René R. Bisonette, Julius Apuy, Brian E. Cathers, Stacie S. Canan, Mehran F. Moghaddam, Heather K. Raymon, Peter Worland, Rama Krishna Narla, Kimberly E. Fultz, Sabita Sankar
We report here the synthesis and structure–activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino­[2,3-b]­pyrazine-2­(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1­(pS6) and mTORC2­(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.