Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active RORγ inverse agonists. Issue 14 (15th July 2019)

• Record Type: Journal Article
• Authors: Amaudrut, Jérôme; Argiriadi, Maria A.; Barth, Martine; Breinlinger, Eric C.; Bressac, Didier; Broqua, Pierre; Calderwood, David J.; Chatar, Mohamed; Cusack, Kevin P.; Gauld, Stephen B.; Jacquet, Sébastien; Kamath, Rajesh V.; Kort, Michael E.; Lepais, Valérie; Luccarini, Jean-Michel; Masson, Philippe; Montalbetti, Christian; Mounier, Laurent; Potin, Dominique; Poupardin, Olivia; Rouaud, Sylvie; Spitzer, Luc; Wallace, Craig D.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 14(2019)
• Page Start: 1799
• Page End: 1806
• Publication Date: 2019-07-15
• Subjects: RORγt inverse agonist -- Th17 cells -- IL-17 -- Nuclear hormone receptor -- SAR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.05.015
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein.