Saroglitazar

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). The EC50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARa and hPPARc are 0.65 pmol/L and 3 nmol/L, respectively.^[1]

HepG2 cells are seeded in 12-well plates at a density of 400,000 cells/well in 1 mL of medium per well. Cells are transfected with PPRE3-TK-luc and 0.08 μg of the pCDNA expression vector containing the cDNA of PPARa or 0.08 μg of the pSG5 expression vector containing the cDNA of PPARc using Superfect. Cells are incubated at 37 ℃, 5% CO2: 95% O2 and after 3 h 1.0 mL of the medium containing Saroglitazar are added to the respective wells. After the incubation for 20–22 h at 37 ℃ under 5% CO2, cells are first washed with Phosphate Buffer Saline (pH 7.3- 7.4), lysed and supernatant collected for luciferase and bgalactosidase activity. The luciferase activity is determined using commercial firefly luciferase assay according to the suppliers’ instructions in white 96-well plate. The bgalactosidase activity is determined in ELISA reader at 415 nm.

In db/db mice, 12-day treatment with Saroglitazar (0.01–3 mg/kg per day, orally) causes dose-dependent reductions in serum triglycerides (TG), free fatty acids (FFA), and glucose. The ED50 for these effects is 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%) is also observed in Zucker fa/fa rats, Swiss albino mice, and in high fat -high cholesterol (HF-HC)-fed Golden Syrian hamsters. LDL cholesterol is 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 demonstrates potent insulin-sensitizing activity. Saroglitazar also shows 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 confirms efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans.^[1]