Reduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3891-7. doi: 10.1016/j.bmcl.2014.06.048. Epub 2014 Jun 25.

Abstract

Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma-protein unbound fraction and improvements in cellular permeability and aqueous solubility.

Keywords: IL-17; Permeability; RORc; RORγ; Solubility; X-ray structure.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Blood Proteins / chemistry*
  • Blood Proteins / metabolism
  • Cell Membrane Permeability / drug effects*
  • Crystallography, X-Ray
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Madin Darby Canine Kidney Cells
  • Models, Molecular
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Rats
  • Solubility
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Blood Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Sulfonamides