gw-7647 and Metabolic-Syndrome

Topics: Animals; Humans; Ligands; Metabolic Syndrome; Models, Molecular; Molecular Targeted Therapy; Peroxisome Proliferator-Activated Receptors

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

Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type γ (PPARγ). Simultaneous modulation of sEH and PPARγ can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARγ pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 μM/PPARγ EC50 = 0.3 μM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS.

Topics: 3T3 Cells; Administration, Oral; Animals; Benzamides; Chlorocebus aethiops; COS Cells; Diabetes Mellitus, Type 2; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Hypertension; In Vitro Techniques; Metabolic Syndrome; Mice; Microsomes, Liver; PPAR gamma; Rats; Structure-Activity Relationship