In vitro activity: BMS-687453 shows negligible activity (EC50 for transactivation of>25 μM and efficacies of<15% of standard) against a panel of human nuclear hormone receptors, including PPARδ LXR and RXR. BMS-687453 as a potent, highly selective PPARalpha agonist with an excellent preclinical safety profile.

Kinase Assay: BMS-687453 is a potent and selective PPARα agonist, with an EC50 and IC50 of 10 nM and 260 nM for human PPARα and 4100 nM and>15000 nM for PPARγ in PPAR-GAL4 transactivation assays. A homogeneous, fluorescent polarization PPARα and PPARγ binding assay is used as the primary screen for determining the PPARα and PPARγ binding affinity of compounds. The human functional activity of PPARα and PPARγ agonists is determined by using the GAL4-LBD assays. The in vitro hamster, rat, and mouse PPARα functional activities are tested in the chimeric GAL4/PPARα assay format. The data are reported as an EC50value calculated using XLfit 4 parameter fit and floating all parameters. Full length human PPARα and PPARγ co-transfection assays in HepG2 cells are employed for further testing the leading compounds (BMS-687453)

Cell Assay: BMS-687453 exhibits high PPARα potency (EC50 = 47 nM) with ~50-fold selectivity vs PPARγ (EC50 = 2400 nM) in HepG2 cells. However, BMS-687453 shows less potent activities in rodent PPARα functional assays, with a moderate EC50 of 426 nM for mouse and 488 nM for hamster but remains a full PPARα agonist in both species.