We investigated the
biological activity of Dr. Reddy's Research Foundation (
DRF) 2519, a
benzoxazinone analogue of the
thiazolidinedione class of compounds. In the in vitro transactivation assay,
DRF 2519 showed interesting dual activation of
Peroxisome Proliferator Activated Receptor (
PPAR) alpha and gamma. In
insulin-resistant ob/ob mouse model,
DRF 2519 showed significant alleviation of
insulin resistance and
dyslipidemia, which is better than
rosiglitazone. Fatty Zucker rats treated with
DRF 2519 showed better reduction of plasma
insulin,
triglyceride and
free fatty acid levels than those treated with
rosiglitazone. In addition, these rats were able to clear plasma
lipids better when challenged with exogenous
lipid (i.v.).
DRF 2519 treatment resulted in improved plasma
lipid profiles in high-fat-fed Sprague-Dawley rats. Treated rats showed better plasma
lipid clearance and hepatic
triglyceride secretion. When compared to
DRF 2519,
fenofibrate was comparatively less efficacious while rosigltiazone showed no activity in these models. In ex vivo studies,
DRF 2519 showed induction of liver
acyl CoA oxidase mRNA and increase in
lipoprotein lipase (LPL)
protein expression and activity in adipose tissue. In the in vitro studies,
DRF 2519 inhibited the
lipid biosynthesis and secretion of
apolipoprotein B from human
hepatoma (Hep)G2 cells. It also enhanced
insulin-induced relaxation of rat aortic smooth muscle. These results indicate that
DRF 2519, a dual activator of
PPAR-alpha and gamma, could be an interesting development candidate in the management of metabolic disorders and associated complications.