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.
Benaïssa BoubiaOlivia PoupardinMartine BarthJean BinetPhilippe PeralbaLaurent MounierElise JacquierEmilie GauthierValérie LepaisMaryline ChatarStéphanie FerryAnne ThourignyFabrice GuillierJonathan LlacerJérôme AmaudrutPierre DodeyOlivier LacombePhilippe MassonChristian MontalbettiGuillaume WettsteinJean-Michel LuccariniChristiane LegendreJean-Louis JunienPierre BroquaPublished in: Journal of medicinal chemistry (2018)
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.