Discovery of soluble epoxide hydrolase inhibitors through DNA-encoded library technology (ELT)

Bioorg Med Chem. 2021 Jul 1:41:116216. doi: 10.1016/j.bmc.2021.116216. Epub 2021 May 13.

Abstract

Inhibition of soluble epoxide hydrolase (sEH) has recently emerged as a new approach to treat cardiovascular disease and respiratory disease. Inhibitors based on 1,3,5-triazine chemotype were discovered through affinity selection against two triazine-based DNA-encoded libraries. The structure and activity relationship study led to the expansion of the original 1,4-cycloalkyl series to related aniline, piperidine, quinoline, aryl-ether and benzylic series. The 1,3-cycloalkyl chemotype led to the discovery of a clinical candidate (GSK2256294) for COPD.

Keywords: DNA-encoded library technology; Soluble epoxide hydrolase.

MeSH terms

  • Cyclohexylamines / chemistry
  • Cyclohexylamines / pharmacology*
  • Drug Discovery
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Humans
  • Molecular Structure
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Small Molecule Libraries
  • Triazines / chemistry
  • Triazines / pharmacology*

Substances

  • Cyclohexylamines
  • N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide
  • Small Molecule Libraries
  • Triazines
  • Epoxide Hydrolases