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KMID : 0043320140370091130
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Archives of Pharmacal Research
2014 Volume.37 No. 9 p.1130 ~ p.1138
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ALK inhibitors of bis-ortho-alkoxy-para-piperazinesubstituted-pyrimidines and -triazines for cancer treatment
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Lee Hyeon-Ji
Latif Muhammad
Choe Hyeon-Jeong
Ali Imran
Lee Heung-Kyoung
Yang Eun-Hye
Yun Jeong-In
Chae Chong-Hak
Jung Jae-Kyung
Kim Hyoung-Rae
Lee Chong-Ock
Park Chi-Hoon
Lee Kwang-Ho
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Abstract
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Syntheses of various bis-ortho-alkoxy-para-piperazineanilino-pyrimidines and -triazines of KRCA-0008 analogs are described and their structure?activity-relationship to anaplastic lymphoma kinase (ALK) is discussed. 5-trifluoromethyl-2,4-pyrimidine analog (2) seems to be most potent in both biochemical and cellular assay in this study, however it shows inferior mice xenograft activity to Crizotinib presumably due to its sub-optimal PK parameters. 4,6-disubstituted pyrimidine and 2,4-disubstituted triazine derivatives of KRCA-0008 are less potent or inactive to ALK wt., and this observation is explained with their molecular modeling compared to KRCA-0008.
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KEYWORD
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ALK, Kinases, Diaminopyrimidine, Diaminotriazine, Inhibitors
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