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Antidiabetic and hypolipidemic potential of DRF 2519--a dual activator of PPAR-alpha and PPAR-gamma.

Abstract
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.
AuthorsRanjan Chakrabarti, Parimal Misra, Reeba K Vikramadithyan, Mamnoor Premkumar, Jagadheshan Hiriyan, Srinivas R Datla, Ravi K B Damarla, Juluri Suresh, Ramanujam Rajagopalan
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 491 Issue 2-3 Pg. 195-206 (May 03 2004) ISSN: 0014-2999 [Print] Netherlands
PMID15140637 (Publication Type: Comparative Study, Journal Article)
CopyrightCopyright 2004 Elsevier B.V.
Chemical References
  • DRF 2519
  • Hypoglycemic Agents
  • Hypolipidemic Agents
  • PPAR alpha
  • PPAR gamma
  • Thiazolidinediones
  • Triglycerides
Topics
  • Animals
  • Aorta, Thoracic (drug effects, physiology)
  • Dose-Response Relationship, Drug
  • Humans
  • Hypoglycemic Agents (chemistry, pharmacology)
  • Hypolipidemic Agents (chemistry, pharmacology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • PPAR alpha (agonists, metabolism)
  • PPAR gamma (agonists, metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Rats, Zucker
  • Thiazolidinediones (chemistry, pharmacology)
  • Triglycerides (blood)

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