Pharmacological profile of a novel, non‐TZD PPARγ agonist

Aim:  The purpose of this study was to characterize a novel, non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR)γ agonist, RWJ-348260, via both in vitro and in vivo approaches. Methods:  The in vitro PPARγ activities of RWJ-348260 were assessed in PPARγ-GAL4 co-transfection assay, PPARγ receptor binding assay, aP2 gene induction assay and preadipocyte differentiation assay. The in vivo efficacy of the compound was determined in rodent genetic diabetes models [ob/ob mouse, db/db mouse and Zucker diabetic fatty (ZDF) rat] following multiple days of oral administration. Results:  RWJ-348260 selectively activated PPARγin vitro. In vivo, RWJ-348260 produced significant decreases in plasma glucose, HbA1c, insulin and triglyceride levels. RWJ-348260 also dose-dependently improved oral glucose tolerance. In db/db mice, the compound up-regulated PPARγ target genes in white adipose tissues. RWJ-348260 produced a lower extent of hepatocyte lipid deposition and a smaller increase in liver weight compared to rosiglitazone in db/db mice. While RWJ-348260 effectively normalized hyperglycaemia and dyslipidaemia, it did not change haematocrit, transaminase, alkaline phosphatase, total bilirubin levels or liver weights in ZDF rats. Conclusions:  RWJ-348260 is a potent PPARγ agonist with efficacious antidiabetic activity in diabetic animal models. The compound has an improved side-effect profile compared to rosiglitazone.