Ragaglitazar: a novel PPAR alpha PPAR gamma agonist with potent lipid-lowering and insulin-sensitizing efficacy in animal models

Abstract

Ragaglitazar [(-) DRF 2725; NNC 61-0029] is a coligand of PPARalpha and PPARgamma. In ob/ob mice, ragaglitazar showed significant reduction in plasma glucose, triglyceride and insulin (ED50 values <0.03, 6.1 and <0.1 mg kg-1). These effects are three-fold better than rosiglitazone and KRP-297. In Zucker fa/fa rats, ragaglitazar showed dose-dependent reduction in triglyceride and insulin, hepatic triglyceride secretion and triglyceride clearance kinetics (maximum of 74, 53, 32 and 50% at 3 mg kg-1), which are better than rosiglitazone and KRP-297. In a high-fat-fed hyperlipidaemic rat model, the compound showed an ED50 of 3.95, 3.78 mg kg-1 for triglyceride and cholesterol lowering, and 0.29 mg kg-1 for HDL-C increase. It also showed improvement in clearance of plasma triglyceride and hepatic triglyceride secretion rate. All these effects are 3-10-fold better than fenofibrate and KRP-297. Ragaglitazar treatment showed significant reduction in plasma Apo B and Apo CIII levels, and increase in liver CPT1 and CAT activity and ACO mRNA. Significant increase of both liver and fat LPL activity and fat aP2 mRNA was also observed. In a high-fat-fed hamster model, ragaglitazar at 1 mg kg-1 showed 83 and 61% reduction in triglyceride and total cholesterol, and also 17% reduction in fat feed-induced body weight increase. In these hyperlipidaemic animal models, PPARgamma ligands failed to show any significant efficacy. Taken together, ragaglitazar shows better insulin-sensitizing and lipid-lowering potential, as compared to the standard compounds.

Figure 1

Activation of (a) PPARγ and (b) PPARα by ragaglitazar. HEK 293T cells were transfected with Gal4-PPARγ1 or PPARα-LBD, pGL2(Gal 4X5)-SV 40-Luc reporter and pAdvantage constructs. The values are an average of three experiments conducted in triplicate.

Figure 2

Effect of ragaglitazar on glucose tolerance test in ob/ob mice. Animals were treated with the compound at 0.3, 1, 3 and 10 mg kg⁻¹ dose for 9 days, and then subjected to oral glucose load (3 gm kg⁻¹) after a 5 h fast. The values are expressed as mean±s.e.m. (n=5); *P<0.05 as compared to control (ANOVA).

Figure 3

Effect of ragaglitazar on (a) hepatic triglyceride secretion and (b) plasma triglyceride clearance in Zucker fa/fa rats. Animals were treated with the compound for 9 days, and injected with triton WR 1339 or 20% intralipid, as described in Methods. The values are expressed as mean±s.e. (n=5); *P<0.05 as compared to control (ANOVA).

Figure 4

Effect of ragaglitazar on plasma (a) total cholesterol, (b) triglyceride, (c) HDL-C and (d) LDL-C in high-fat-fed rats. Animals were kept on high-fat diet, and compound treatment was done for 6 days at 0.1, 0.3, 1, 10 and 30 mg kg⁻¹. The values are expressed as mean±s.e. (n=5); *P<0.05 as compared to control (ANOVA).

Figure 5

Effect of ragaglitazar on (a) hepatic triglyceride secretion and (b) plasma triglyceride clearence in high-fat-fed rats. Animals were treated with the compound at 3 mg kg⁻¹ for 6 days, and injected with triton or 20% intralipid, as described in Methods. The values are expressed as mean±s.e. (n=5); *P<0.05 as compared to control (ANOVA).

Figure 6

Induction of aP2 and ACO mRNA. High-fat-fed rats were treated with ragaglitazar (3 mg kg⁻¹), rosiglitazone and fenofibrate (both at 30 mg kg⁻¹) for 6 days. Extraction of RNA and RT–PCR procedure as described in Methods. (a) Represents aP2 mRNA (top panel), and the corresponding β-actin (bottom panel). (b) Represents ACO mRNA (top panel) and β-actin (bottom panel). Lane 1: control; 2: ragaglitazar; 3: fenofibrate and 4: rosiglitazone.