Ragaglitazar: a novel PPARα & PPARγ agonist with potent lipid‐lowering and insulin‐sensitizing efficacy in animal models

• Published in: British journal of pharmacology Vol. 140; no. 3; pp. 527 - 537
• Main Authors: Chakrabarti, Ranjan, Vikramadithyan, Reeba K, Misra, Parimal, Hiriyan, Jagadheshan, Raichur, Suryaprakash, Damarla, Ravi K, Gershome, Cynthia, Suresh, Juluri, Rajagopalan, Ramanujam
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2003; Nature Publishing
• Subjects: Animals; Antidiabetic; Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hyperlipidemias - blood; Hyperlipidemias - drug therapy; Hyperlipidemias - genetics; hypolipidaemic; Insulin - blood; insulin sensitizer; Lipids - blood; Male; Medical sciences; Mesocricetus; Mice; Mice, Inbred C57BL; Mice, Obese; Oxazines - pharmacology; Oxazines - therapeutic use; peroxisome proliferator‐activated receptor (PPAR); Pharmacology. Drug treatments; Phenylpropionates - pharmacology; Phenylpropionates - therapeutic use; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - physiology; Transcription Factors - agonists; Transcription Factors - physiology; Triglycerides - blood; Animal model; Pancreatic hormone; Agonist; Ragaglitazar; Antidiabetic; Lipids; Insulin; peroxisome proliferator-activated receptor (PPAR); hypolipidaemic; Hypoglycemic agent; Chemosensitizing agent; Peroxisome proliferator activated receptor; insulin sensitizer; Antilipemic agent
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705463

Ragaglitazar [(−) DRF 2725; NNC 61‐0029] is a coligand of PPARα and PPARγ. In ob/ob mice, ragaglitazar showed significant reduction in plasma glucose, triglyceride and insulin (ED50 values <0.03, 6.1 and <0.1 mg kg−1). These effects are three‐fold better than rosiglitazone and KRP‐297. In Zucker fa/fa rats, ragaglitazar showed dose‐dependent reduction in triglyceride and insulin, hepatic triglyceride secretion and triglyceride clearance kinetics (maximum of 74, 53, 32 and 50% at 3 mg kg−1), which are better than rosiglitazone and KRP‐297. In a high‐fat‐fed hyperlipidaemic rat model, the compound showed an ED50 of 3.95, 3.78 mg kg−1 for triglyceride and cholesterol lowering, and 0.29 mg kg−1 for HDL‐C increase. It also showed improvement in clearance of plasma triglyceride and hepatic triglyceride secretion rate. All these effects are 3–10‐fold better than fenofibrate and KRP‐297. Ragaglitazar treatment showed significant reduction in plasma Apo B and Apo CIII levels, and increase in liver CPT1 and CAT activity and ACO mRNA. Significant increase of both liver and fat LPL activity and fat aP2 mRNA was also observed. In a high‐fat‐fed hamster model, ragaglitazar at 1 mg kg−1 showed 83 and 61% reduction in triglyceride and total cholesterol, and also 17% reduction in fat feed‐induced body weight increase. In these hyperlipidaemic animal models, PPARγ ligands failed to show any significant efficacy. Taken together, ragaglitazar shows better insulin‐sensitizing and lipid‐lowering potential, as compared to the standard compounds. British Journal of Pharmacology (2003) 140, 527–537. doi:10.1038/sj.bjp.0705463