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
  • 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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