Identification and Preclinical Pharmacology of the -Secretase Modulator BMS-869780
BMS-869780 dose response and evaluation of residual Aβ levels in rat brain. (a) Groups of rats received intraperitoneal (IP) injections of vehicle or BMS-869780 at doses of 100, 30, 10, 3, 1, and 0.3 mg/kg. Additional rats were dosed with GSI BMS-698861 at 30 mg/kg as a positive control for Aβ-lowering. Group sizes were seven rats for each dose of BMS-869780 and 14 rats for vehicle and GSI dose groups. Brain and plasma were harvested 5 hours after dosing. Brain Aβ1-42 (green), brain Aβ1-40 (blue), brain Aβ1-x (black), and plasma Aβ1-40 (red) were determined. Values are expressed as % relative to vehicle group mean. Whiskers represent standard error. Aβ1-x was not determined in the groups dosed at 3, 1, and 0.3 mg/kg. (b) Brain Aβ1-40 was plotted against brain Aβ1-42 for each rat dosed with BMS-869780 (black ▼) and for each rat dosed with vehicle (grey ●). Values are expressed as % relative to vehicle group mean. Whiskers represent standard error. (c) Brain Aβ1-42 (●), brain Aβ1-40 (■), and plasma Aβ1-40 (▲) were plotted against plasma concentration of BMS-869780 and the data were evaluated by fit to a four-parameter dose response curve. The top of the dose response curve was defined by vehicle group mean (100%), and the apparent IC50 values in terms of the plasma BMS-869780 concentration obtained for brain Aβ1-42, brain Aβ1-40, and plasma Aβ1-40 were 807 nM, 943 nM, and 84 nM, respectively. The respective 95% confidence intervals were 618–1053 nM, 704–1264 nM, and 44–158 nM. (d) Rats were dosed once daily with BMS-869780 for 4 days at 10 and 100 mg/kg or vehicle, plasma, and brain samples were taken 5 hours after the last dose, and immunodepletion of brain extracts was carried out prior to Aβ1-42 ELISA assays. Specific monoclonals used were 565 (Aβ1-42 selective), TSD (Aβ1-40 selective), 4G8 (binds both Aβ1-42 and Aβ1-40), and 6E10 (does not bind rat Aβ). After immunodepletion, Aβ1-42 was assayed by ELISA. (e) Same as described in (d), except that Aβ1-40 ELISA was carried out following the immunodepletion.
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