gft505 and Metabolic-Syndrome

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver steatosis, inflammation, and hepatocellular damage. NASH is a serious condition that can progress to cirrhosis, liver failure, and hepatocellular carcinoma. The association of NASH with obesity, type 2 diabetes mellitus, and dyslipidemia has led to an emerging picture of NASH as the liver manifestation of metabolic syndrome. Although diet and exercise can dramatically improve NASH outcomes, significant lifestyle changes can be challenging to sustain. Pharmaceutical therapies could be an important addition to care, but currently none are approved for NASH. Here, we review the most promising targets for NASH treatment, along with the most advanced therapeutics in development. These include targets involved in metabolism (e.g., sugar, lipid, and cholesterol metabolism), inflammation, and fibrosis. Ultimately, combination therapies addressing multiple aspects of NASH pathogenesis are expected to provide benefit for patients.

Topics: Animals; Anticholesteremic Agents; Drug Delivery Systems; Drug Development; Humans; Hypoglycemic Agents; Lipid Metabolism; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; PPAR gamma; Protein Structure, Tertiary

The peroxisome proliferator-activated receptors (PPARs) exert vital function in the regulation of energy metabolism, which were considered as promising targets of metabolic syndrome. Until now, PPARδ/γ dual agonist is rarely reported, and thereby the pharmacologic action of PPARδ/γ dual agonist is still unclear. In this study, we identified a dual PPARδ/γ partial agonist 6 (ZLY06) based on the cyclization strategy of PPARα/δ dual agonist GFT505. ZLY06 revealed excellent pharmacokinetic profiles suitable for oral medication. Moreover, ZLY06 markedly improved glucolipid metabolism without weight gain, and alleviated fatty liver by promoting the β-oxidation of fatty acid and inhibiting hepatic lipogenesis. In contrast, weight gain and hepatic steatosis were observed in Rosiglitazone, a widely used PPARγ full agonist. All of these results indicated that ZLY06 exhibits potential benefits on metabolic syndrome, while no adverse effects related to PPARγ full agonist.

Topics: Animals; Diabetes Mellitus, Experimental; Diet, High-Fat; Dose-Response Relationship, Drug; Drug Discovery; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Molecular Structure; Organic Chemicals; PPAR delta; PPAR gamma; Rats; Rats, Sprague-Dawley; Streptozocin; Structure-Activity Relationship