Identification and Preclinical Pharmacology of the -Secretase Modulator BMS-869780
Analysis of the PK/PD relationship for BMS-869780 in rats and mice. Rats were dosed orally with BMS-869780 at 10 mg/kg, and triple transgenic mice were orally dosed at 30 mg/kg and 100 mg/kg. Additional groups of rats and mice were dosed with vehicle alone. Brain and plasma were harvested at 3, 5, 8, 16, and 24 hours after dosing for determination of brain Aβ1-42 and plasma BMS-869780 concentration. Group sizes were 5 rats or 4 mice. Whiskers represent standard error. (a) Plasma concentrations of BMS-869780 were determined for the mice dosed at 100 mg/kg (▲) and 30 mg/kg (■) and for the rats dosed at 10 mg/kg (▼). The data were fit to a one-compartment PK model and the predicted plasma BMS-869780 concentrations are shown for mouse (solid lines) and rat (broken line). (b) Brain Aβ1-42 levels were determined for the mice dosed with BMS-869780 at 100 mg/kg (▲), 30 mg/kg (■), or vehicle alone (●). The data were fitted using the indirect pharmacodynamic response model and predicted values are shown (solid lines). (c) Brain Aβ1-42 levels were determined for the rats dosed with BMS-869780 at 10 mg/kg (▼) or vehicle alone (●). The data were fitted using the indirect pharmacodynamic response model and predicted values are shown (dashed line). The values of the PK and PD parameters determined from these experiments are summarized in Table 2. (d) Brain Aβ1-40 levels determined in the same rats as illustrated in (c).
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