5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach

Bioorg Med Chem. 2019 Sep 1;27(17):3745-3759. doi: 10.1016/j.bmc.2019.06.040. Epub 2019 Jul 4.

Abstract

The most common inflammatory disease of the airways is asthma among children affecting around 235 million people worldwide. 5-Lipoxygenase (5-LOX) is a crucial enzyme which helps in the conversion of arachidonic acid (AA) to leukotrienes (LTs), the lipid mediators. It is associated with several inflammation related disorders such as asthma, allergy, and atherosclerosis. Therefore, it is considered as a promising target against inflammation and asthma. Currently, the only drug against 5-LOX which is available is Zileuton, while a few inhibitors are in clinical trial stages such as Atreleuton and Setileuton. So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades.

Keywords: 5-LOX/COX/mPGES-1; Arachidonic acid; Inhibitors; Leukotrienes; Prostaglandins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Leukotrienes / metabolism
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Leukotrienes
  • Lipoxygenase Inhibitors
  • Arachidonate 5-Lipoxygenase