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.
Subject(s)
Benzothiazoles/chemical synthesis , Benzothiazoles/pharmacology , Fibrosis/prevention & control , Indoles/chemical synthesis , Indoles/pharmacology , Peroxisome Proliferator-Activated Receptors/agonists , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Benzothiazoles/pharmacokinetics , Carbon Tetrachloride Poisoning/drug therapy , Cell Line , Drug Discovery , Hepatocytes/drug effects , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Indoles/pharmacokinetics , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Non-alcoholic Fatty Liver Disease/drug therapy , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/pharmacokineticsABSTRACT
In the search for new orally active antithrombotic drugs that are metabolically stable, we explored the synthesis of 1-C-(5-thio-D-xylosyl) derivatives, examining radical and nucleophilic methods. Thus synthesized were aryl, benzyl, alkylcarboxymethylenyl, arylsulfonylmethylenyl and alkylaminocarboxymethylenyl C-linked analogues of 5-thio-D-xylopyranosides.
