Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis.
Gilles OuvryNicolas Atrux-TallauFranck BihlAline BonduClaire Bouix-PeterIsabelle CarlavanOlivier ChristinMarie-Josée CuadradoClaire Defoin-PlatelSophie DeretDenis DuvertChristophe FeretMathieu ForissierJean-François FournierDavid FroudeFériel Hacini-RachinelCraig Steven HarrisCatherine HervouetHélène HuguetGuillaume LafitteAnne-Pascale LuzyBranislav MusickiDanielle OrfilaBenjamin OzelloCoralie PascauJonathan PascauVéronique ParnetGuillaume PeluchonRomain PierreDavid PiwnicaCatherine RaffinPatricia RossioDelphine SpiesseNathalie TaquetEtienne ThoreauRodolphe VatinelEmmanuel VialLaurent François HennequinPublished in: ChemMedChem (2018)
With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.