Discovery and optimization of potent and selective benzonaphthyridinone analogs as small molecule mTOR inhibitors with improved mouse microsome stability

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Liu, Qingsong^1,2  Wang, Jinhua^1,2  Kang, Seong A.^3,5  Thoreen, Carson C.^1,2  Hur, Wooyoung^1,2  Choi, Hwan Geun^1,2  Waller, David L.^1,2  Sim, Taebo^1,2  Sabatini, David M.^3,4,5  Gray, Nathanael S.^1,2 

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[4] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA

[5] MIT, Koch Ctr Integrat Canc Res, Cambridge, MA 02139 USA

关键词: mTOR;    PI3K;    Torin1;   

DOI  :  10.1016/j.bmcl.2011.04.129

来源: Elsevier

【 摘 要 】

Starting from small molecule mTOR inhibitor Torin1, replacement of the piperazine ring with a phenyl ring resulted in a new series of mTOR inhibitors (as exemplified by 10) that showed superior potency and selectivity for mTOR, along with significantly improved mouse liver microsome stability and a longer in vivo half-life. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

Free