A novel selective peroxisome proliferator-activator receptor-γ modulator—SPPARγM5 improves insulin sensitivity with diminished adverse cardiovascular effects

The use of the thiazolidinedione insulin sensitizers rosiglitazone and pioglitazone for the treatment of type 2 diabetes mellitus in recent years has proven to be effective in helping patients resume normal glycemic control. However, their use is often associated with undesirable side effects including peripheral edema, congestive heart failure and weight gain. Here, we report the identification and characterization of a novel selective PPARγ modulator, SPPARγM5 ((2S)-2-(2-chloro-5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl} phenoxy)propionic acid), which has notable insulin sensitizing properties and a superior tolerability profile to that of rosiglitazone. SPPARγM5 is a potent ligand of human PPARγ with high selectivity versus PPARα or PPARδ in receptor competitive binding assays. In cell-based transcriptional activation assays, SPPARγM5 was a potent partial agonist of human PPARγ in comparison to the PPARγ full agonist rosiglitazone. Compared to rosiglitazone or the PPARγ full agonist COOH (2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid), SPPARγM5 induced an attenuated PPARγ-regulated gene expression profile in fully differentiated 3T3-L1 adipocytes and white adipose tissue of chronically treated db/db mice. SPPARγM5 treatment also reduced the insulin resistance index by homeostasis model assessment (HOMA), suggesting an improvement in insulin resistance in these db/db mice. Treatment of obese Zucker rats with either rosiglitazone or SPPARγM5 resulted in an improvement in selected parameters that serve as surrogate indicators of insulin resistance and hyperlipidemia. However, unlike rosiglitazone, SPPARγM5 did not cause significant fluid retention or cardiac hypertrophy in these rats. Thus, compounds such as SPPARγM5 may offer beneficial effects on glycemic control with significantly attenuated adverse effects.