ORIGINAL ARTICLE Saroglitazar, a novel PPARa/c agonist with predominant PPARa activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models Mukul R. Jain 1 , Suresh R. Giri 1 , Chitrang Trivedi 1 , Bibhuti Bhoi 1 , Akshyaya Rath 1 , Geeta Vanage 2 , Purvi Vyas 1 , Ramchandra Ranvir 1 & Pankaj R. Patel 1 1 Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad 382 213, Gujarat, India 2 National Institute for Research in Reproductive Health, Parel, Mumbai, India Keywords Anti-diabetic, dual PPAR agonist, glitazar, hypertriglyceridemia, insulin sensitizer, lipaglyn Correspondence Mukul R. Jain, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla Highway No.8A, Moraiya, Ahmedabad 382 213, Gujarat, India. Tel: +91 2717 665555; Fax: +91 2717 665355; E-mail: mukul.jain@zyduscadila.com Funding Information This work was financially supported by Cadila Healthcare Limited, Ahmedabad, India. Received: 28 January 2015; Revised: 10 February 2015; Accepted: 12 February 2015 Pharma Res Per, 3(3), 2015, e00136, doi: 10.1002/prp2.136 doi: 10.1002/prp2.136 ZRC communication # 465. Part of this work was presented at the 72nd Scientific Sessions of the American Diabetes Association (ADA), Philadelphia, PA, USA; 8–12 June 2012. Abstract Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid deriva- tive designed to act as dual regulator of lipids and glucose metabolism by acti- vating peroxisome proliferator-activated receptors (PPAR). These studies evaluate the efficacy and safety profile of Saroglitazar in preclinical in vitro and in vivo models. The EC 50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARa and hPPARc were 0.65 pmol/L and 3 nmol/L, respectively. In db/db mice, 12-day treatment with Saroglitazar (0.01–3 mg/kg per day, orally) caused dose-dependent reductions in serum tri- glycerides (TG), free fatty acids (FFA), and glucose. The ED 50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose. Significant reduction in serum TG (upto 90%) was also observed in Zucker fa/fa rats, Swiss albino mice, and in high fat -high cholesterol (HF-HC)-fed Golden Syrian hamsters. LDL choles- terol was significantly lowered in hApoB100/hCETP double transgenic mice and HF-HC diet fed Golden Syrian Hamsters. Hyperinsulinemic-Euglycemic clamp study in Zucker fa/fa rats demonstrated potent insulin-sensitizing activity. Sa- roglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats. A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associ- ated side effects in humans. Based on efficacy and safety profile, Saroglitazar appears to have good potential as novel therapeutic agent for treatment of dysl- ipidemia and diabetes. Abbreviations ACO, acyl-CoA oxidase; ACRP30, adipocyte complement-related protein of 30 kDa; aP2, adipocyte fatty acid-binding protein; CETP, cholesteryl ester transfer protein; FATP, fatty acid transporter protein; GIR, glucose infusion rate; HDL-C, high-density lipoprotein cholesterol; HF-HC, high fat-high cholesterol; IVLTT, intravenous lipid tolerance test; LDL-C, low-density lipoprotein cholesterol; LPL, lipoprotein lipase; NIN, National institute of nutrition; NIRRH, National institute for research in reproductive health; OGTT, oral glucose tolerance test; PPAR, per- oxisome proliferator–activated receptors; SAM, swiss albino mice; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; ZRC, Zydus research centre. ª 2015 Cadila Healthcare LTD. India., Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 2015 | Vol. 3 | Iss. 3 | e00136 Page 1