Identification and Preclinical Pharmacology of the -Secretase Modulator BMS-869780
BMS-869780 modulated Aβ but did not cause accumulation of βCTF or αCTF in rat brain. Rats were given oral doses of BMS-869780, and levels of brain Aβ, βCTF, and αCTF were determined 24 hours later. For comparison, BMS-698861 was dosed in a separate experiment and samples were taken 5 hours later. (a) Brain levels of Aβ1-42 (red), Aβ1-40 (green), Aβ1-38 (blue), and Aβ1-37 (purple) are shown as bars stacked upon one another. The total height of each bar therefore represents the sum of the four peptides. (b) Aβ1-42 (red—left Y axis) and Aβ1-x (grey—right Y axis). The same results for Aβ1-42 are plotted in both (a) and (b). (c) Rat brain βCTF was detected by western blotting of immunoprecipitates from samples of the same rat brains used for Aβ determinations. V, vehicle groups; results from rats dosed with 1.9, 22, 100, and 235 mg/kg of BMS-869780 and 10 mg/kg BMS-698861 (GSI) are indicated. (d) Western blots of immunoprecipitated αCTF from the same rat brain samples. (e) and (f) quantification of western blots shown in (c) and (d), respectively, expressed relative to percent of average level of CTF in vehicle-treated rats. Actual doses of BMS-869780 were determined by analysis of concentrations in left-over dosing solutions.
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