Open AccessSaroglitazar, a novel PPAR α / γ agonist with predominant PPAR α activity, shows lipid‐lowering and insulin‐sensitizing effects in preclinical models
Author(s) -
Jain Mukul R.,
Giri Suresh R.,
Trivedi Chitrang,
Bhoi Bibhuti,
Rath Akshyaya,
Vanage Geeta,
Vyas Purvi,
Ranvir Ramchandra,
Patel Pankaj R.
Publication year - 2015
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.136
Subject(s) - endocrinology , medicine , chemistry , insulin , peroxisome proliferator activated receptor , pioglitazone , cholesterol , agonist , adiponectin , pharmacology , receptor , diabetes mellitus , insulin resistance , type 2 diabetes
Abstract Saroglitazar is a novel nonthiazolidinediones ( TZD ) and nonfibric acid derivative designed to act as dual regulator of lipids and glucose metabolism by activating 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 hPPAR α and hPPAR γ 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 triglycerides ( 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 cholesterol was significantly lowered in hA poB100/ 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. Saroglitazar 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 ‐associated side effects in humans. Based on efficacy and safety profile, Saroglitazar appears to have good potential as novel therapeutic agent for treatment of dyslipidemia and diabetes.