title: 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.
authors.affiliation: Discovery Biology, Dr. Reddy's Laboratory-Discovery Research, Bollaram Road, Miyapur, Hyderabad 500 049, India. ranjanchakrabatri@drreddys.com
authors.forename: Ranjan
authors.initials: R
authors.lastname: Chakrabarti
authors.forename: Parimal
authors.initials: P
authors.lastname: Misra
authors.forename: Reeba K
authors.initials: RK
authors.lastname: Vikramadithyan
authors.forename: Mamnoor
authors.initials: M
authors.lastname: Premkumar
authors.forename: Jagadheshan
authors.initials: J
authors.lastname: Hiriyan
authors.forename: Srinivas R
authors.initials: SR
authors.lastname: Datla
authors.forename: Ravi K B
authors.initials: RK
authors.lastname: Damarla
authors.forename: Juluri
authors.initials: J
authors.lastname: Suresh
authors.forename: Ramanujam
authors.initials: R
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011924:Rats, Zucker; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: C495944:DRF 2519; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides