Structure-activity relationship study of β-oxidation resistant indole-based 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) receptor antagonists

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4770-4776. doi: 10.1016/j.bmcl.2017.08.034. Epub 2017 Aug 19.

Abstract

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is formed from 5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) by the 5-lipoxygenase (5-LO) pathway under conditions associated with oxidative stress. 5-Oxo-ETE is an important pro-inflammatory mediator, which stimulates the migration of eosinophils via a selective G-protein coupled receptor, known as the OXE receptor (OXE-R). Previously, we designed and synthesized structural mimics of 5-oxo-ETE such as 1 using an indole scaffold. In the present work, we added various substituents at C-3 of this moiety to block potential β-oxidation of the 5-oxo-valerate side chain, and investigated the structure-activity relationships of the resulting novel β-oxidation-resistant antagonists. Cyclopropyl and cyclobutyl substituents were well tolerated in this position, but were less potent as the highly active 3S-methyl compound. It seems likely that 3-alkyl substituents can affect the conformation of the 5-oxovalerate side chain containing the critical keto and carboxyl groups, thereby affecting interaction with the OXE-receptor.

Keywords: 5-Oxo-ETE; Antagonist; Asthma; Eosinophil; Structure-activity relationship.

Publication types

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

MeSH terms

  • Arachidonate 5-Lipoxygenase / metabolism
  • Drug Design
  • Eosinophils / cytology
  • Eosinophils / metabolism
  • Humans
  • Indoles / chemistry
  • Indoles / metabolism*
  • Inhibitory Concentration 50
  • Oxidation-Reduction
  • Receptors, Eicosanoid / antagonists & inhibitors*
  • Receptors, Eicosanoid / metabolism
  • Static Electricity
  • Structure-Activity Relationship

Substances

  • Indoles
  • Receptors, Eicosanoid
  • Arachidonate 5-Lipoxygenase