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

Eur J Med Chem. 2015 Apr 13:94:265-75. doi: 10.1016/j.ejmech.2015.03.007. Epub 2015 Mar 5.

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.

Keywords: Enzyme kinetics; Expression; Inhibitor; Lipoxygenase; Salicylate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 15-Lipoxygenase / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Kinetics
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Salicylates / chemical synthesis
  • Salicylates / chemistry
  • Salicylates / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2-((4-((3,7-dimethyloctyl)oxy)benzyl)oxy)-6-hydroxybenzoic acid
  • Lipoxygenase Inhibitors
  • Salicylates
  • ALOX15 protein, human
  • Arachidonate 15-Lipoxygenase