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

European Journal of Medicinal Chemistry
Nikolaos EleftheriadisFrank J Dekker

Abstract

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.

References

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Citations

Sep 4, 2015·Journal of Medicinal Chemistry·Nikolaos EleftheriadisFrank J Dekker
Feb 10, 2017·PloS One·Atena JabbariHamid Sadeghian
Sep 10, 2016·Angewandte Chemie·Nikolaos EleftheriadisFrank J Dekker
Jan 10, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Thalia LiargkovaDimitra Hadjipavlou-Litina
Jul 30, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Adam R Offenbacher, Theodore R Holman
Jun 25, 2019·Helvetica Chimica Acta·Deka PrismawanAnna K H Hirsch
Apr 10, 2019·Journal of Medicinal Chemistry·Hao GuoFrank J Dekker

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