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 PPAR gamma modulator, SPPAR gamma M5 ((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. SPPAR gamma M5 is a potent ligand of human PPAR gamma with high selectivity versus PPAR alpha or PPAR6 in receptor competitive binding assays. In cell-based transcriptional activation assays, SPPAR gamma M5 was a potent partial agonist of human PPAR gamma in comparison to the PPAR gamma full agonist rosiglitazone. Compared to rosiglitazone or the PPAR gamma full agonist COOH (2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid), SPPAR gamma M5 induced an attenuated PPAR gamma-regulated gene expression profile in fully differentiated 3T3-L1 adipocytes and white adipose tissue of chronically treated db/db mice. SPPAR gamma M5 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 SPPAR gamma M5 resulted in an improvement in selected parameters that serve as surrogate indicators of insulin resistance and hyperlipidemia. However, unlike rosiglitazone, SPPAR gamma M5 did not cause significant fluid retention or cardiac hypertrophy in these rats. Thus, compounds such as SPPARM5 gamma may offer beneficial effects on glycemic control with significantly attenuated adverse effects. (c) 2008 Elsevier B.V. All rights reserved.