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.
MeSH terms
-
Animals
-
Benzothiazoles / chemical synthesis*
-
Benzothiazoles / pharmacokinetics
-
Benzothiazoles / pharmacology*
-
Carbon Tetrachloride Poisoning / drug therapy
-
Cell Line
-
Drug Discovery
-
Fibrosis / prevention & control*
-
Hepatocytes / drug effects
-
High-Throughput Screening Assays
-
Humans
-
Hypoglycemic Agents / chemical synthesis
-
Hypoglycemic Agents / pharmacology
-
Indoles / chemical synthesis*
-
Indoles / pharmacokinetics
-
Indoles / pharmacology*
-
Mice
-
Mice, Inbred C57BL
-
Models, Molecular
-
Molecular Structure
-
Non-alcoholic Fatty Liver Disease / drug therapy
-
Peroxisome Proliferator-Activated Receptors / agonists*
-
Rats
-
Rats, Sprague-Dawley
-
Structure-Activity Relationship
-
Sulfonamides / chemical synthesis*
-
Sulfonamides / pharmacokinetics
-
Sulfonamides / pharmacology*
Substances
-
Benzothiazoles
-
Hypoglycemic Agents
-
Indoles
-
Peroxisome Proliferator-Activated Receptors
-
Sulfonamides
-
lanifibranor