warfarin and Carbon-Tetrachloride-Poisoning

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.

Topics: Animals; Benzothiazoles; Carbon Tetrachloride Poisoning; Cell Line; Drug Discovery; Fibrosis; Hepatocytes; High-Throughput Screening Assays; Humans; Hypoglycemic Agents; Indoles; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Structure; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Sulfonamides

Topics: Animals; Antipyrine; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Half-Life; Liver; Male; Rabbits; Warfarin

After hepatic injury induced by carbon tetrachloride, mitotically active hematopoietic cells of nonhepatic origin localize in the liver as judged by an increase in colony-forming nodules in the spleens of lethally irradiated recipient mice on intravenous injection of cells from these livers. The administration of warfarin suppresses the localization of colony-forming units in the regenerating liver by inhibiting the coagulation mechanism of the donor animals.

Topics: Animals; Blood Coagulation; Bone Marrow Cells; Carbon Tetrachloride Poisoning; Female; In Vitro Techniques; Liver Regeneration; Mice; Spleen; Subcellular Fractions; Vitamin K; Warfarin