Euglycemic and hypolipidemic activity of PAT5A: A unique thiazolidinedionewith weak peroxisome proliferator activated receptor gamma activity

The euglycemic and hypolipidemic activities of PAT5A, a novel pyridine anal og of thiazolidinedione, have been evaluated in different animal models. Ad ministration of PAT5A to db/db mice resulted in dose-dependent decreases in plasma glucose, triglyceride, and insulin levels, and an improved glucose tolerance. The glucose-lowering activity of PAT5A was better than that of t roglitazone and comparable to that of rosiglitazone. In addition, PAT5A sho wed better lipid-lowering activity than troglitazone or rosiglitazone. A si milar profile was seen in ob/ob mice. in high-fat-fed Sprague Dawley rats, PAT5A treatment reduced plasma triglyceride and total cholesterol levels. A n in vitro peroxisome proliferator activated receptor gamma (PPAR gamma) tr ansactivation assay in HEK-293 cells showed poor transactivation for PAT5A compared with rosiglitazone. PAT5A did not show any PPAR alpha- or PPAR del ta -activating properties. Ex vivo study in db/db mice treated with PAT5A s howed decreased activity of liver glucose g-phosphatase, a key enzyme in gl uconeogenesis. A 28-day probe toxicity study in Wistar rats did not show an y treatment-related alterations in hematologic and biochemical parameters, nor any macroscopic and microscopic changes in the vital organs, whereas ro siglitazone treatment increased liver and heart weights. Our results indica te that PAT5A is a potent insulin sensitizer and hypolipidemic compound wit h a weak PPAR gamma activation potential. Both in vivo and in vitro results suggest that PAT5A improves glucose kinetics and lipid levels through mech anisms not related to PPAR activation. Copyright (C) 2000 by W.B. Saunders Company.