A Peroxisome Proliferator-Activated Receptor α/γ Dual Agonist with a Unique in Vitro Profile and Potent Glucose and Lipid Effects in Rodent Models of Type 2 Diabetes and Dyslipidemia

Abstract

LSN862 is a novel peroxisome proliferator-activated receptor (PPAR)alpha/gamma dual agonist with a unique in vitro profile that shows improvements on glucose and lipid levels in rodent models of type 2 diabetes and dyslipidemia. Data from in vitro binding, cotransfection, and cofactor recruitment assays characterize LSN862 as a high-affinity PPARgamma partial agonist with relatively less but significant PPARalpha agonist activity. Using these same assays, rosiglitazone was characterized as a high-affinity PPARgamma full agonist with no PPARalpha activity. When administered to Zucker diabetic fatty rats, LSN862 displayed significant glucose and triglyceride lowering and a significantly greater increase in adiponectin levels compared with rosiglitazone. Expression of genes involved in metabolic pathways in the liver and in two fat depots from compound-treated Zucker diabetic fatty rats was evaluated. Only LSN862 significantly elevated mRNA levels of pyruvate dehydrogenase kinase isozyme 4 and bifunctional enzyme in the liver and lipoprotein lipase in both fat depots. In contrast, both LSN862 and rosiglitazone decreased phosphoenol pyruvate carboxykinase in the liver and increased malic enzyme mRNA levels in the fat. In addition, LSN862 was examined in a second rodent model of type 2 diabetes, db/db mice. In this study, LSN862 demonstrated statistically better antidiabetic efficacy compared with rosiglitazone with an equivalent side effect profile. LSN862, rosiglitazone, and fenofibrate were each evaluated in the humanized apoA1 transgenic mouse. At the highest dose administered, LSN862 and fenofibrate reduced very low-density lipoprotein cholesterol, whereas, rosiglitazone increased very low-density lipoprotein cholesterol. LSN862, fenofibrate, and rosiglitazone produced maximal increases in high-density lipoprotein cholesterol of 65, 54, and 30%, respectively. These findings show that PPARgamma full agonist activity is not necessary to achieve potent and efficacious insulin-sensitizing benefits and demonstrate the therapeutic advantages of a PPARalpha/gamma dual agonist.

Peroxisome Proliferator–Activated Receptor (PPAR)α Activation Increases Adiponectin Receptors and Reduces Obesity-Related Inflammation in Adipose Tissue

“…It was recently reported that a PPAR␣/␥ agonist elevated pyruvate dehydrogenase kinase isozyme 4 (PDK4) mRNA levels in liver compared with vehicle or a PPAR␥ agonist (42). In the present study, we checked PDK4 mRNA levels in liver and epididymal adipose tissue and found that PDK4 mRNA levels in epididymal adipose tissue of Wy-14,643-treated KKAy mice were significantly higher than those of vehicle-treated KKAy mice (data not shown), indicating that PPAR␣ was actually activated in adipose tissue by Wy-14,643 treatment.…”

Two Thiophenes Compounds Are Partial Peroxisome Proliferator-Activated Receptor .ALPHA./.GAMMA. Dual Agonists

“…16,17) In recent years, several structurally diverse PPAR dual agonists or PPAR pan agonists have been discovered. [17][18][19][20][21][22] Although several of them have been discontinued because of various side effects such as carcinogenesis in preclinical murine models, the effects of some new class of dual and pan PPAR agonists on the regulation of glucose and lipid metabolism with improved safety patterns have been demonstrated in experimental animal models.…”

“…20,21) Hence novel PPARa/g dual agonists are promising agents to combat metabolic disease with better profile. 17) In addition, partial PPAR agonists with modest response such as metaglidasen are developed in many companies including Metabolex, Roche, Evolva, and Astellas, with the goal of retaining beneficial effects of this class of agents while diminishing their adverse effects.…”

Structure and physiological functions of the human peroxisome proliferator-activated receptor γ

“…It was recently reported that a PPAR-γ partial agonist similar to LSN862, i.e. (S)-2 methoxy-3-{4-[5-(4-phenoxy)pent--1-ynyl]phenyl}-propionic acid, has better antidiabetic activity and weaker side effects than the TZDs [98]. More recently, a novel family of PPAR-γ partial agonists (pyrazol-5-yl benzenesulfonamide derivatives) with either high potency or specificity in vitro or glucose-lowering efficacy in vivo has been identified [75].…”