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Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models.

Jain MR, Giri SR, Trivedi C, Bhoi B, Rath A, Vanage G, Vyas P, Ranvir R, Patel PR - Pharmacol Res Perspect (2015)

Bottom Line: The ED50 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.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.

View Article: PubMed Central - PubMed

Affiliation: Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India.

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 EC50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARα and hPPARγ 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 ED50 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 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. 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.

No MeSH data available.


Related in: MedlinePlus

Structural formula of Saroglitazar and its in vitro activation. (A) Structural formula of Saroglitazar (B) Activation of PPARα and (C) activation of PPARγ by Saroglitazar. HepG2 cells were transfected with PPRE3-TK-luc and 0.08 μg of the cDNA (3.1) expression vector containing the cDNA of PPARα or 0.08 μg of the pSG5 expression vector containing the cDNA of PPARγ. The values are an average of duplicate experiments.
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fig01: Structural formula of Saroglitazar and its in vitro activation. (A) Structural formula of Saroglitazar (B) Activation of PPARα and (C) activation of PPARγ by Saroglitazar. HepG2 cells were transfected with PPRE3-TK-luc and 0.08 μg of the cDNA (3.1) expression vector containing the cDNA of PPARα or 0.08 μg of the pSG5 expression vector containing the cDNA of PPARγ. The values are an average of duplicate experiments.

Mentions: Saroglitazar, [(S)-α-ethoxy-4-{2-[2-methyl-5-(4- methylthio) phenyl)]-1H-pyrrol-1-yl]-ethoxy})-benzenepropanoic acid magnesium salt] (Fig.1A), rosiglitazone and fenofibrate were synthesized by Cadila Healthcare Limited, Ahmedabad, India. WY14, 643 was procured from Sigma-Aldrich Co. LLC (St. Louis, MO, USA).


Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models.

Jain MR, Giri SR, Trivedi C, Bhoi B, Rath A, Vanage G, Vyas P, Ranvir R, Patel PR - Pharmacol Res Perspect (2015)

Structural formula of Saroglitazar and its in vitro activation. (A) Structural formula of Saroglitazar (B) Activation of PPARα and (C) activation of PPARγ by Saroglitazar. HepG2 cells were transfected with PPRE3-TK-luc and 0.08 μg of the cDNA (3.1) expression vector containing the cDNA of PPARα or 0.08 μg of the pSG5 expression vector containing the cDNA of PPARγ. The values are an average of duplicate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492752&req=5

fig01: Structural formula of Saroglitazar and its in vitro activation. (A) Structural formula of Saroglitazar (B) Activation of PPARα and (C) activation of PPARγ by Saroglitazar. HepG2 cells were transfected with PPRE3-TK-luc and 0.08 μg of the cDNA (3.1) expression vector containing the cDNA of PPARα or 0.08 μg of the pSG5 expression vector containing the cDNA of PPARγ. The values are an average of duplicate experiments.
Mentions: Saroglitazar, [(S)-α-ethoxy-4-{2-[2-methyl-5-(4- methylthio) phenyl)]-1H-pyrrol-1-yl]-ethoxy})-benzenepropanoic acid magnesium salt] (Fig.1A), rosiglitazone and fenofibrate were synthesized by Cadila Healthcare Limited, Ahmedabad, India. WY14, 643 was procured from Sigma-Aldrich Co. LLC (St. Louis, MO, USA).

Bottom Line: The ED50 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.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.

View Article: PubMed Central - PubMed

Affiliation: Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India.

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 EC50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARα and hPPARγ 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 ED50 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 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. 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.

No MeSH data available.


Related in: MedlinePlus