Identification of 6-benzyloxysalicylates as a novel class of inhibitors of 15-lipoxygenase-1

Nikolaos Eleftheriadis, Stephanie Thee, Johan Te Biesebeek, Petra van der Wouden, Bert-Jan Baas, Frank J Dekker

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Lipoxygenases metabolize polyunsaturated fatty acids into signalling molecules such as leukotrienes and lipoxins. 15-lipoxygenase-1 (15-LOX-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 Ki value of 1.7 μM. These structure activity relationships provide a basis to design improved inhibitors and to explore 15-LOX-1 as a drug target.

Original languageEnglish
Pages (from-to)265-275
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 13-Apr-2015

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