Selective Optimization of Pranlukast to Farnesoid X Receptor Modulators

ChemMedChem. 2018 Dec 6;13(23):2530-2545. doi: 10.1002/cmdc.201800549. Epub 2018 Nov 20.

Abstract

Selective optimization of side activities (SOSA) offers an alternative entry to early drug discovery and may provide rapid access to bioactive new chemical entities with desirable properties. SOSA aims to reverse a drug's side activities through structural modification and to design out the drug's original main action. We identified a moderate side activity for the cysteinyl leukotriene receptor 1 (CysLT1 R) antagonist pranlukast on the farnesoid X receptor (FXR). Systematic structural modification of the drug allowed remarkable optimization of its partial FXR agonism to sub-nanonmolar potency. The resulting FXR modulators lack any activity on CysLT1 R and are characterized by high selectivity, high metabolic stability, and low toxicity. With their favorable in vitro profile, these SOSA-derived FXR modulators constitute a new FXR ligand chemotype that appears suitable for further preclinical evaluation.

Keywords: bile acid receptor modulator; non-alcoholic steatohepatitis; selective optimization of side activities (SOSA).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromones / chemistry*
  • Chromones / pharmacology*
  • Drug Discovery / methods
  • Hep G2 Cells
  • Humans
  • Leukotriene Antagonists / chemistry*
  • Leukotriene Antagonists / pharmacology*
  • Ligands
  • Molecular Docking Simulation
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Leukotriene / metabolism
  • Structure-Activity Relationship

Substances

  • Chromones
  • Leukotriene Antagonists
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Leukotriene
  • farnesoid X-activated receptor
  • leukotriene D4 receptor
  • pranlukast