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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