title: Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists.
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.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Fauber.Benjamin@gene.com.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Robarge
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Aihe
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Barnard
authors.affiliation: ChemPartner, No. 5 Building, 998 Halei Road, Zhangjiang Hi-Tech Park Pudong New Area, Shanghai 201203, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Cao
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Céline
authors.initials: C
authors.lastname: Eidenschenk
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Everett
authors.affiliation: Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors.forename: Arunima
authors.initials: A
authors.lastname: Ganguli
authors.affiliation: Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Hawkins
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.affiliation: Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors.forename: Maxine
authors.initials: M
authors.lastname: Norman
authors.affiliation: Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Salmon
authors.affiliation: Argenta, Units 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Summerhill
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: ChemPartner, No. 5 Building, 998 Halei Road, Zhangjiang Hi-Tech Park Pudong New Area, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D020381:Interleukin-17 / Q000276:immunology; D008099:Liver / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000276:immunology; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C508717:IL17A protein, human; D007093:Imidazoles; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011725:Pyridines; D011743:Pyrimidines
keywords: GNE-0946; GNE-6468; IL-17; PPARγ; RORc; RORγ