2. Academic Validation
  3. Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists

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

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.
  • 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.

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