Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A(4) Hydrolyase

doi:10.1021/jm200063s

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	Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A(4) Hydrolyase
	Chen, Zheng; Wu, Yiran; Liu, Ying; Yang, Suijia; Chen, Yunjie; Lai, Luhua
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2011-05-26
卷号	54 期号:10 页码:3650-3660
ISSN号	0022-2623
DOI	10.1021/jm200063s
英文摘要	Dual target inhibitors against COX-2. and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activities using enzyme assays and human whole blood assay. Introduction of small electron withdrawing groups like NO2 and CF3 in the ortho-position of the terminal phenyl ring was found to change the original single target LTA(4)H inhibitor to dual target LTA(4)H and COX-2 inhibitors. Compound 5a and 5m showed dual LTA(4)H and COX-2 inhibition activities in the enzyme assays and the I-EWE assay with IC50 values in the micromolar to submicromolar range. As their activities in HWB assay were comparable to the two starting single target inhibitors, the two compounds are promising for further studies. The strategy used in the current study may be generally applicable to other dual target drug designs.
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000290651800015
内容类型	期刊论文
源URL	[http://ir.iccas.ac.cn/handle/121111/72625]
专题	中国科学院化学研究所
通讯作者	Liu, Ying
作者单位	Peking Univ, Coll Chem & Mol Engn, State Key Lab Struct Chem Unstable & Stable Speci, BNLMS, Beijing 100871, Peoples R China
推荐引用方式 GB/T 7714	Chen, Zheng,Wu, Yiran,Liu, Ying,et al. Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A(4) Hydrolyase[J]. JOURNAL OF MEDICINAL CHEMISTRY,2011,54(10):3650-3660.
APA	Chen, Zheng,Wu, Yiran,Liu, Ying,Yang, Suijia,Chen, Yunjie,&Lai, Luhua.(2011).Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A(4) Hydrolyase.JOURNAL OF MEDICINAL CHEMISTRY,54(10),3650-3660.
MLA	Chen, Zheng,et al."Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A(4) Hydrolyase".JOURNAL OF MEDICINAL CHEMISTRY 54.10(2011):3650-3660.