Identification and Preclinical Pharmacology of the -Secretase Modulator BMS-869780
BMS-869780 caused PXR activation in vitro and lipidosis in rat liver. (a) PXR activation in the presence of BMS-869780 was evaluated in HepG2 cell cultures using a luciferase transcriptional reporter construct (●), or by assay of CYP3A4 mRNA levels in primary human hepatocyte (PHH) cultures from two individual donors (▲ and ▼). Activation in both assays is expressed as % relative to activation in the presence of rifampicin, 10 μM, in parallel cultures. (b) Liver section from vehicle-dosed rats. (c) Liver section from rats given 4 daily doses of BMS-869780 at 100 mg/kg. A summary of the plasma BMS-869780 exposures from this experiment is shown in Table 5.
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