期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 94, 期 -, 页码 265-275出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.03.007
关键词
Lipoxygenase; Expression; Inhibitor; Enzyme kinetics; Salicylate
资金
- Netherlands Organisation for Scientific Research (NWO) [016.122.302]
Lipoxygenases metabolize polyunsaturated fatty acids into signalling molecules such as leukotrienes and lipoxins. 15-lipoxygenase-1 (15LOX-1) is an important mammalian lipoxygenase and plays a crucial regulatory role in several respiratory diseases such as asthma, COPD and chronic bronchitis. Novel potent and selective inhibitors of 15-LOX-1 are required to explore the role of this enzyme in drug discovery. In this study we describe structure activity relationships for 6-benzyloxysalicylates as inhibitors of human 15-LOX-1. Kinetic analysis suggests competitive inhibition and the binding model of these compounds can be rationalized using molecular modelling studies. The most potent derivative 37a shows a K-i value of 1.7 mu M. These structure activity relationships provide a basis to design improved inhibitors and to explore 15-LOX-1 as a drug target. (C) 2015 Elsevier Masson SAS. All rights reserved.
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