Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis

  • ChemMedChem. 2018 Feb 20;13(4):321-337. doi: 10.1002/cmdc.201700758.
Gilles Ouvry  1 Nicolas Atrux-Tallau  1 Franck Bihl  1 Aline Bondu  1 Claire Bouix-Peter  1 Isabelle Carlavan  1 Olivier Christin  1 Marie-Josée Cuadrado  1 Claire Defoin-Platel  1 Sophie Deret  1 Denis Duvert  1 Christophe Feret  1 Mathieu Forissier  1 Jean-François Fournier  1 David Froude  1 Fériel Hacini-Rachinel  1 Craig Steven Harris  1 Catherine Hervouet  1 Hélène Huguet  1 Guillaume Lafitte  1 Anne-Pascale Luzy  1 Branislav Musicki  1 Danielle Orfila  1 Benjamin Ozello  1 Coralie Pascau  1 Jonathan Pascau  1 Véronique Parnet  1 Guillaume Peluchon  1 Romain Pierre  1 David Piwnica  1 Catherine Raffin  1 Patricia Rossio  1 Delphine Spiesse  1 Nathalie Taquet  1 Etienne Thoreau  1 Rodolphe Vatinel  1 Emmanuel Vial  1 Laurent François Hennequin  1
Affiliations
  • 1. Nestlé Skin Health R&D, 2400 Route des Colles, BP 87, 06902, Sophia-Antipolis Cedex, France.
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-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.

Keywords
RORγ; interleukin 17; lipophilic ligand efficiency; psoriasis; topical application.
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