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

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-alpha transactivation compared with reference agonists, which showed concentration-dependent transactivation against human PPAR-alpha 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-alpha in a concentration-dependent manner. The known PPAR-delta 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 (300 mu M) showed no response in mouse and rat and a marginal response against human PPAR-delta receptors (3.2-fold). For PPAR-gamma, gemcabene showed no agonist activity against all 3 species at 100 mu M and marginal activity (3.6-to 5-fold) at 300 mu M. By contrast, the known agonists, rosiglitazone, indomethacin, and muraglitazar showed strong activation against the mouse, rat, and human PPAR-gamma receptors. No clear antagonist activity was observed with gemcabene against any PPAR subtypes for all 3 species over a wide range of concentrations. In summary, the transactivation studies rule out gemcabene as a direct agonist or antagonist of PPAR-alpha, PPAR-gamma, and PPAR-delta receptors of these 3 species. These data suggest that the peroxisomal effects observed in rodents and the lipid regulating effects observed in rodents and humans are not related to a direct activation of PPAR receptors by gemcabene.