2. Academic Validation
  3. Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active RORγ inverse agonists

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.
Jérôme Amaudrut 1,  Maria A Argiriadi 2,  Martine Barth 1,  Eric C Breinlinger 2,  Didier Bressac 1,  Pierre Broqua 1,  David J Calderwood 3,  Mohamed Chatar 1,  Kevin P Cusack 2,  Stephen B Gauld 4,  Sébastien Jacquet 1,  Rajesh V Kamath 3,  Michael E Kort 4,  Valérie Lepais 1,  Jean-Michel Luccarini 1,  Philippe Masson 1,  Christian Montalbetti 1,  Laurent Mounier 1,  Dominique Potin 5,  Olivia Poupardin 1,  Sylvie Rouaud 1,  Luc Spitzer 1,  Craig D Wallace 3
Affiliations

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.

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