Identification of tertiary sulfonamides as RORc inverse agonists

Benjamin P Fauber; Olivier René; Brenda Burton; Christine Everett; Alberto Gobbi; Julie Hawkins; Adam R Johnson; Marya Liimatta; Peter Lockey; Maxine Norman; Harvey Wong

doi:10.1016/j.bmcl.2014.03.038

Identification of tertiary sulfonamides as RORc inverse agonists

Bioorg Med Chem Lett. 2014 May 1;24(9):2182-7. doi: 10.1016/j.bmcl.2014.03.038. Epub 2014 Mar 21.

Affiliations

¹ Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Fauber.Benjamin@gene.com.
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: 24685544
DOI: 10.1016/j.bmcl.2014.03.038

Abstract

Screening a nuclear receptor compound subset in a RORc biochemical binding assay revealed a benzylic tertiary sulfonamide hit. Herein, we describe the identification of compounds with improved RORc biochemical inverse agonist activity and cellular potencies. These improved compounds also possessed appreciable selectivity for RORc over other nuclear receptors.

Keywords: Autoimmune; IL-17; Inflammation; RORc; RORγ.

MeSH terms

Humans
Ligands
Molecular Docking Simulation
Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / pharmacology*

Substances

Ligands
Nuclear Receptor Subfamily 1, Group F, Member 3
RORC protein, human
Sulfonamides