Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists

  • Bioorg Med Chem Lett. 2015 Aug 1;25(15):2907-12. doi: 10.1016/j.bmcl.2015.05.055.
Benjamin P Fauber  1 ,  Alberto Gobbi  2 ,  Kirk Robarge  2 ,  Aihe Zhou  2 ,  Adrian Barnard  3 ,  Jianhua Cao  4 ,  Yuzhong Deng  2 ,  Céline Eidenschenk  2 ,  Christine Everett  2 ,  Arunima Ganguli  3 ,  Julie Hawkins  3 ,  Adam R Johnson  2 ,  Hank La  2 ,  Maxine Norman  3 ,  Gary Salmon  3 ,  Susan Summerhill  3 ,  Wenjun Ouyang  2 ,  Wei Tang  4 ,  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.
  • 4. ChemPartner, No. 5 Building, 998 Halei Road, Zhangjiang Hi-Tech Park Pudong New Area, Shanghai 201203, China.
PMID: 26048793 DOI: 10.1016/j.bmcl.2015.05.055
Abstract

The nuclear receptor (NR) retinoic acid receptor-related Orphan Receptor gamma (RORγ, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPARγ, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology.

Keywords
GNE-0946; GNE-6468; IL-17; PPARγ; RORc; RORγ.
Products