Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active RORγ inverse agonists

[Display omitted] 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 aft...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 29; no. 14; pp. 1799 - 1806
Main 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.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 15-07-2019
Subjects:	IL-17 Nuclear hormone receptor RORγt inverse agonist SAR Th17 cells Nuclear hormone receptor RORγt inverse agonist SAR IL-17 Th17 cells
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Summary:	[Display omitted] 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2019.05.015