Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis. (6th February 2018)

• Record Type: Journal Article
• Authors: Ouvry, Gilles; Atrux‐Tallau, Nicolas; Bihl, Franck; Bondu, Aline; Bouix‐Peter, Claire; Carlavan, Isabelle; Christin, Olivier; Cuadrado, Marie‐Josée; Defoin‐Platel, Claire; Deret, Sophie; Duvert, Denis; Feret, Christophe; Forissier, Mathieu; Fournier, Jean‐François; Froude, David; Hacini‐Rachinel, Fériel; Harris, Craig Steven; Hervouet, Catherine; Huguet, Hélène; Lafitte, Guillaume; Luzy, Anne‐Pascale; Musicki, Branislav; Orfila, Danielle; Ozello, Benjamin; Pascau, Coralie; Pascau, Jonathan; Parnet, Véronique; Peluchon, Guillaume; Pierre, Romain; Piwnica, David; Raffin, Catherine; Rossio, Patricia; Spiesse, Delphine; Taquet, Nathalie; Thoreau, Etienne; Vatinel, Rodolphe; Vial, Emmanuel; Hennequin, Laurent François;
• Is Part Of: ChemMedChem. Volume 13:Number 4(2018)
• Page Start: 321
• Page End: 337
• Publication Date: 2018-02-06
• Subjects: interleukin 17 -- lipophilic ligand efficiency -- psoriasis -- RORγ -- topical application; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700758
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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‐2 H ‐pyran‐4‐yl)methyl]‐2, 3‐dihydro‐1 H ‐benzo[ d ]imidazole‐5‐sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL‐23‐induced mouse skin inflammation model. Abstract : You′re gonna hear me ROR ! The pressure is on to find RORγ modulators, which show promise in the treatment of autoimmune diseases, specifically psoriasis. The optimization of heterobicyclic sulfonamides is presented here with a focus on minimizing lipophilicity. These efforts culminated in the identification of CD12681, a potent RORγ inverse agonist compatible with topical application and efficacy in vivo.