P633H, a novel dual agonist at peroxisome proliferator‐activated receptors α and γ, with different anti‐diabetic effects in db/db and KK‐Ay mice

BACKGROUND AND PURPOSE: Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of type 2 diabetes and the metabolic syndrome. P633H (2-[4-(2-Fluoro-benzenesulphonyl)-piperazin-1-yl]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid), a novel PPARalpha/gamma dual agonist, was investigated for its very different effects on insulin resistance and dyslipidemia in db/db and KK-A(y) mice. EXPERIMENTAL APPROACH: The action of P633H at PPARalpha/gamma was characterized by using transactivation assays. Functional activation of PPARalpha/gammain vitro was confirmed by pre-adipocyte differentiation and regulation of target gene expression. Anti-diabetic studies were performed in two different diabetic mice models in vivo. KEY RESULTS: P633H activated both PPARalpha and PPAR gamma, (with EC(50) values of 0.012 micromol and 0.032 micromol respectively). Additionally, P633H promoted pre-adipocyte differentiation, up-regulated expression of adipose specific transport protein (aP2) mRNA (3T3-Ll cells) and acyl-CoA oxidase mRNA (LO2 cells). In db/db mice, P633H reduced serum glucose, insulin, triglycerides, non-esterified fatty acids and liver triglycerides. It also improved glucose intolerance without affecting food intake and body weight after 15 days of treatment. However in KK-A(y) mice, hyperglycaemia, dyslipidemia and impaired glucose tolerance were not relieved even after a 25 day treatment with P633H. Further studies with real-time PCR and electron microscopy revealed that P633H promoted progression of diabetes in KK-A(y) mice by increasing hepatic gluconeogenesis and exacerbating pancreatic pathology. CONCLUSION AND IMPLICATIONS: Although P633H was a high-potency PPARalpha/gamma dual agonist, with good functional activity in vitro, it produced opposing anti-diabetic effects in db/db and KK-A(y) mice.