title: Discovery of biaryls as RORγ inverse agonists by using structure-based design.
abstract: RORγ plays a critical role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including T cells, γδ T cells, and innate lymphoid cells. RORγ-mediated inflammation has been linked to susceptibility to Crohn's disease, arthritis, and psoriasis. Thus inverse agonists of RORγ have the potential of modulating inflammation. Our goal was to optimize two RORγ inverse agonists: T0901317 from literature and 1 that we obtained from internal screening. We used information from internal X-ray structures to design two libraries that led to a new biaryl series.
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA. Electronic address: istvan.enyedy@biogen.com.
authors.forename: Istvan J
authors.initials: IJ
authors.lastname: Enyedy
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA.
authors.forename: Noel A
authors.initials: NA
authors.lastname: Powell
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Caravella
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: van Vloten
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA.
authors.forename: Daliya
authors.initials: D
authors.lastname: Banerjee
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Marcotte
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Silvian
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: McKenzie
authors.affiliation: Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, Republic of Korea.
authors.forename: Victor Sukbong
authors.initials: VS
authors.lastname: Hong
authors.affiliation: Biogen, 250 Binney St., Cambridge, MA 02142, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Fontenot
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D006845:Hydrocarbons, Fluorinated; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: Biaryls; RORγ; Retinoid-related orphan receptor gamma; Sulfonamides; Tetrahydroquinolines