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.
Benjamin P Fauber  1 ,  Olivier René  2 ,  Gladys de Leon Boenig  2 ,  Brenda Burton  3 ,  Yuzhong Deng  2 ,  Céline Eidenschenk  2 ,  Christine Everett  2 ,  Alberto Gobbi  2 ,  Sarah G Hymowitz  2 ,  Adam R Johnson  2 ,  Hank La  2 ,  Marya Liimatta  2 ,  Peter Lockey  3 ,  Maxine Norman  3 ,  Wenjun Ouyang  2 ,  Weiru Wang  2 ,  Harvey Wong  2
Affiliations
  • 1. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].
  • 2. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 3. Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
PMID: 25017032 DOI: 10.1016/j.bmcl.2014.06.048
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.