Apr 6, 2018

Comparative Evaluation of Gemcabene and Peroxisome Proliferator-Activated Receptor Ligands in Transcriptional Assays of Peroxisome Proliferator-Activated Receptors: Implication for the Treatment of Hyperlipidemia and Cardiovascular Disease

Journal of Cardiovascular Pharmacology
Charles BisgaierRai Ajit K Srivastava

Abstract

Gemcabene, a late-stage clinical candidate, has shown efficacy for LDL-C, non-HDL cholesterol, apoB, triglycerides, and hsCRP reduction, all risk factors for cardiovascular disease. In rodents, gemcabene showed changes in targets, including apoC-III, apoA-I, peroxisomal enzymes, considered regulated through peroxisome proliferator-activated receptor (PPAR) gene activation, suggesting a PPAR-mediated mechanism of action for the observed hypolipidemic effects observed in rodents and humans. In the current study, the gemcabene agonist activity against PPAR subtypes of human, rat, and mouse were compared with known lipid lowering PPAR activators. Surprisingly, gemcabene showed no or little PPAR-α transactivation compared with reference agonists, which showed concentration-dependent transactivation against human PPAR-α of 2.4- to 30-fold (fenofibric acid), 17-fold (GW590735), and 2.3- to 25-fold (WY-14643). These agents also showed robust transactivation of mouse and rat PPAR-α in a concentration-dependent manner. The known PPAR-δ agonists, GW1516, L165041, and GW0742, showed potent agonist activity against human, mouse, and rat receptors (ranging from 165- to 396-fold). By contrast, gemcabene at the highest concentration tested (30...Continue Reading

  • References49
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Citations

Mentioned in this Paper

PPARA
Study
Regulation of Lipid Metabolic Process
PPARA wt Allele
Transfection
Fenofibric acid
Derivatives
Peroxisome Proliferator-Activated Receptors
Enzymes, antithrombotic
Lobule III

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