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A combinatorial approach for the discovery of drug-like inhibitors of 15-lipoxygenase-1

van der Vlag, R., Guo, H., Hapko, U., Eleftheriadis, N., Monjas, L., Dekker, F. J. & Hirsch, A. K. H., 15-Jul-2019, In : European Journal of Medicinal Chemistry. 174, p. 45-55 11 p.

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  • Final aut- A Combinatorial Approach for the Discovery of Drug-Like Inhibitors of 15-Lipoxygenase-1

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  • A combinatorial approach for the discovery of drug-like inhibitors of15-lipoxygenase-1

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DOI

Human 15-lipoxygenase-1 (15-LOX-1) is a mammalian lipoxygenase which plays an important regulatory role in several CNS and inflammatory lung diseases. To further explore the role of this enzyme in drug discovery, novel potent inhibitors with favorable physicochemical properties are required. In order to identify such new inhibitors, we established a combinatorial screening method based on acylhydrazone chemistry. This represents a novel application of combinatorial chemistry focusing on the improvement of physicochemical properties, rather than on potency. This strategy allowed us to efficiently screen 44 reaction mixtures of different hydrazides and our previously reported indole aldehyde core structure, without the need for individual synthesis of all possible combinations of building blocks. Our approach afforded three new inhibitors with IC50 values in the nanomolar range and improved lipophilic ligand efficiency.

Original languageEnglish
Pages (from-to)45-55
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume174
Publication statusPublished - 15-Jul-2019

    Keywords

  • ANTIOXIDANT CAPACITY, LIGAND EFFICIENCY, IN-VITRO, CHEMISTRY, IDENTIFICATION, LIPOXYGENASE, POWER, FRAP, TOOL

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