Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity

Bioorg Med Chem Lett. 2018 Jan 15;28(2):85-93. doi: 10.1016/j.bmcl.2017.12.006. Epub 2017 Dec 5.

Abstract

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds / chemical synthesis
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Liver X Receptors / agonists
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Structure
  • Pregnane X Receptor
  • Propanols / chemical synthesis
  • Propanols / chemistry
  • Propanols / pharmacology*
  • Receptors, Retinoic Acid / agonists*
  • Receptors, Steroid / agonists*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Bridged Bicyclo Compounds
  • Liver X Receptors
  • Pregnane X Receptor
  • Propanols
  • Receptors, Retinoic Acid
  • Receptors, Steroid
  • Sulfonamides
  • retinoic acid receptor gamma
  • hexafluoroisopropanol