title: Discovery of novel pyrazole-containing benzamides as potent RORγ inverse agonists.
abstract: The nuclear receptor RORγ plays a central role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including TH17 cells. RORγ-dependent inflammation has been implicated in the pathogenesis of several major autoimmune diseases and thus RORγ is an attractive target for therapeutic intervention in these diseases. Starting from a lead biaryl compound 4a, replacement of the head phenyl moiety with a substituted aminopyrazole group resulted in a series with improved physical properties. Further SAR exploration led to analogues (e.g., 4j and 5m) as potent RORγ inverse agonists.
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: taowang2@gmail.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Immunology Discovery, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Daliya
authors.initials: D
authors.lastname: Banerjee
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Tonika
authors.initials: T
authors.lastname: Bohnert
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Enyedy
authors.affiliation: Immunology Discovery, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Fontenot
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Guertin
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Jones
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Lin
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Marcotte
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Talreja
authors.affiliation: Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Van Vloten
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D054314:Drug Inverse Agonism; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D001549:Benzamides; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011720:Pyrazoles; C031280:pyrazole; C037689:benzamide
keywords: Autoimmune disease; IL-17; Inflammation; RORγ inverse agonist; Th17 cell