title: Discovery of biaryl carboxylamides as potent RORγ inverse agonists.
abstract: RORγt is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORγ activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORγ inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with RORγ protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORγ inverse agonists, with demonstrated oral bioavailability in rodents.
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States. Electronic address: jianhua.chao@gmail.com.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Istvan
authors.initials: I
authors.lastname: Enyedy
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Kurt
authors.initials: K
authors.lastname: Van Vloten
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Marcotte
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Guertin
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Hutchings
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Noel
authors.initials: N
authors.lastname: Powell
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Howard
authors.initials: H
authors.lastname: Jones
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Tonika
authors.initials: T
authors.lastname: Bohnert
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Chi-Chi
authors.initials: CC
authors.lastname: Peng
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Silvian
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Victor Sukbong
authors.initials: VS
authors.lastname: Hong
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Little
authors.affiliation: Immunology Research, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Daliya
authors.initials: D
authors.lastname: Banerjee
authors.affiliation: Immunology Research, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Liaomin
authors.initials: L
authors.lastname: Peng
authors.affiliation: Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Arthur
authors.initials: A
authors.lastname: Taveras
authors.affiliation: Immunology Research, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Viney
authors.affiliation: Immunology Research, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Fontenot
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D006801:Humans; D006860:Hydrogen Bonding; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D062105:Molecular Docking Simulation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000276:immunology; D051381:Rats
chemical_list: D000577:Amides; D001713:Biphenyl Compounds; D016207:Cytokines; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
keywords: Biaryl carboxylamides; IL-17; RORγt; Retinoid-related orphan receptor gamma t; Th-17