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DOI 10.1021/acs.jmedchem.7b01285

Медицинская библиотека · Journal of medicinal chemistry · 2018

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.

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, Luccarini Jean-Michel, Legendre Christiane, Junien Jean-Louis, Broqua Pierre

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Аннотация

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.

Для цитирования: 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, Luccarini Jean-Michel, Legendre Christiane, Junien Jean-Louis, Broqua Pierre. 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.. Journal of medicinal chemistry. 2018. DOI: 10.1021/acs.jmedchem.7b01285.

Предметные рубрики MeSH

AnimalsBenzothiazolesCarbon Tetrachloride PoisoningCell LineDrug DiscoveryFibrosisHepatocytesHigh-Throughput Screening AssaysHumansHypoglycemic AgentsIndolesMiceMice, Inbred C57BLModels, MolecularMolecular StructureNon-alcoholic Fatty Liver DiseasePeroxisome Proliferator-Activated ReceptorsRatsRats, Sprague-DawleyStructure-Activity RelationshipSulfonamides
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