학술논문
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.
Document Type
Article
Author
Boubia, Benaïssa; Poupardin, Olivia; Barth, Martine; Binet, Jean; Peralba, Philippe; Mounier, Laurent; Jacquier, Elise; Gauthier, Emilie; Lepais, Valérie; Chatar, Maryline; Ferry, Stéphanie; Thourigny, Anne; Guillier, Fabrice; Llacer, Jonathan; Amaudrut, Jérome; Dodey, Pierre; Lacombe, Olivier; Masson, Philippe; Montalbetti, Christian; Wettstein, Guillaume
Source
Subject
*SULFONAMIDES
*PEROXISOME proliferator-activated receptors
*MEDICATION safety
*FATTY liver
*THERAPEUTICS
*PATIENTS
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Language
ISSN
0022-2623
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 PPARa 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. [ABSTRACT FROM AUTHOR]