Discovery of oxa-sultams as RORc inverse agonists showing reduced lipophilicity, improved selectivity and favorable ADME properties

  • Bioorg Med Chem Lett. 2016 Sep 15;26(18):4455-4461. doi: 10.1016/j.bmcl.2016.07.081.
Olivier René  1 ,  Benjamin P Fauber  2 ,  Adrian Barnard  3 ,  Kerry Chapman  3 ,  Yuzhong Deng  2 ,  Céline Eidenschenk  2 ,  Christine Everett  2 ,  Alberto Gobbi  2 ,  Adam R Johnson  2 ,  Hank La  2 ,  Maxine Norman  3 ,  Gary Salmon  3 ,  Susan Summerhill  3 ,  Harvey Wong  2
Affiliations
  • 1. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
  • 2. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 3. Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
PMID: 27524313 DOI: 10.1016/j.bmcl.2016.07.081
Abstract

Modification of the δ-sultam ring of RORc inverse agonist 2 led to the discovery of more polar oxa-sultam 65. The less lipophilic inverse agonist (65) displayed high potency in a biochemical assay, which translated into inhibition of IL-17 production in human peripheral blood mononuclear cells. The successful reduction of lipophilicity of this new analog gave rise to additional improvements in ROR selectivity and aqueous kinetic solubility, as well as reduction in plasma protein binding, while maintaining high cellular permeability.

Keywords
IL-17; Inverse agonist; Oxa-sultam; PBMCs; RORc; RORγ.