Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast

ChemMedChem. 2020 Jan 7;15(1):50-67. doi: 10.1002/cmdc.201900576. Epub 2019 Nov 19.

Abstract

The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non-alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti-NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti-asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver-related metabolic diseases.

Keywords: NAFLD; NASH; Polypharmacology; non-alcoholic steatohepatitis; nuclear receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Cholesterol 7-alpha-Hydroxylase / genetics
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Drug Evaluation, Preclinical
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / genetics
  • Epoxide Hydrolases / metabolism
  • Gene Expression Regulation / drug effects
  • Hep G2 Cells
  • Humans
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Molecular Docking Simulation
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Structure-Activity Relationship
  • Tosyl Compounds / chemistry*
  • Tosyl Compounds / metabolism
  • Tosyl Compounds / pharmacology

Substances

  • Membrane Transport Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Tosyl Compounds
  • farnesoid X-activated receptor
  • Cholesterol 7-alpha-Hydroxylase
  • Epoxide Hydrolases
  • zafirlukast