Design, Synthesis, and Evaluation of a Novel Series of Indole Sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) α/γ/δ Triple Activators: Discovery of Lanifibranor, a New Antifibrotic Clinical Candidate

  • J Med Chem. 2018 Mar 22;61(6):2246-2265. doi: 10.1021/acs.jmedchem.7b01285.
Benaïssa Boubia  1 ,  Olivia Poupardin  1 ,  Martine Barth  1 ,  Jean Binet ,  Philippe Peralba ,  Laurent Mounier  1 ,  Elise Jacquier  1 ,  Emilie Gauthier  1 ,  Valérie Lepais  1 ,  Maryline Chatar  1 ,  Stéphanie Ferry  2 ,  Anne Thourigny ,  Fabrice Guillier  1 ,  Jonathan Llacer  1 ,  Jérome Amaudrut  1 ,  Pierre Dodey ,  Olivier Lacombe  1 ,  Philippe Masson  1 ,  Christian Montalbetti  1 ,  Guillaume Wettstein  1 ,  Jean-Michel Luccarini  1 ,  Christiane Legendre ,  Jean-Louis Junien  1 ,  Pierre Broqua  1
Affiliations
  • 1. Inventiva , 50 rue de Dijon , 21121 Daix , France.
  • 2. Novalix , Boulevard Sebastien Brant Bioparc , 67405 Illkirch , France.
PMID: 29446942 DOI: 10.1021/acs.jmedchem.7b01285
Abstract

Here, we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα Activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR Agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to nonalcoholic steatohepatitis (NASH) pathophysiology suggesting therapeutic potential for NASH patients.