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

Jérôme Amaudrut; Maria A Argiriadi; Martine Barth; Eric C Breinlinger; Didier Bressac; Pierre Broqua; David J Calderwood; Mohamed Chatar; Kevin P Cusack; Stephen B Gauld; Sébastien Jacquet; Rajesh V Kamath; Michael E Kort; Valérie Lepais; Jean-Michel Luccarini; Philippe Masson; Christian Montalbetti; Laurent Mounier; Dominique Potin; Olivia Poupardin; Sylvie Rouaud; Luc Spitzer; Craig D Wallace

doi:10.1016/j.bmcl.2019.05.015

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

Bioorg Med Chem Lett. 2019 Jul 15;29(14):1799-1806. doi: 10.1016/j.bmcl.2019.05.015. Epub 2019 May 9.

Authors

Jérôme Amaudrut¹, Maria A Argiriadi², Martine Barth¹, Eric C Breinlinger², Didier Bressac¹, Pierre Broqua¹, David J Calderwood³, Mohamed Chatar¹, Kevin P Cusack², Stephen B Gauld⁴, Sébastien Jacquet¹, Rajesh V Kamath³, Michael E Kort⁴, Valérie Lepais¹, Jean-Michel Luccarini¹, Philippe Masson¹, Christian Montalbetti¹, Laurent Mounier¹, Dominique Potin⁵, Olivia Poupardin¹, Sylvie Rouaud¹, Luc Spitzer¹, Craig D Wallace³

Affiliations

¹ Inventiva, 50 rue de Dijon, 21121 Daix, France.
² AbbVie, 381 Plantation Street, Worcester, MA 01605, USA.
³ AbbVie, 100 Research Drive, Worcester, MA 01605, USA.
⁴ AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
⁵ Inventiva, 50 rue de Dijon, 21121 Daix, France. Electronic address: [email protected].

PMID: 31101472
DOI: 10.1016/j.bmcl.2019.05.015

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.

Keywords: IL-17; Nuclear hormone receptor; RORγt inverse agonist; SAR; Th17 cells.

MeSH terms

Animals
Disease Models, Animal
Drug Inverse Agonism*
Humans
Mice
Nuclear Receptor Subfamily 1, Group F, Member 3 / chemistry*
Quinolines / chemistry*

Substances

Nuclear Receptor Subfamily 1, Group F, Member 3
Quinolines