BMS 433796

BMS 433796 is a γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer's disease. IC50 & Target: γ-secretase^[1] In Vitro: BMS-433796 cause a concentration-dependent decrease in [³H]IN973 binding, with IC₅₀ value of 1.2 nM, very similar to the IC₅₀ values for inhibition of Aβ40 in human embryonic kidney cells overexpressing the Swedish mutation of APP of 0.8 nM, respectively, and for inhibition of Aβ42 of 0.4 nM, respectively^[2]. In Vivo: BMS 433796 is characterized in pharmacokinetic studies in male Sprague-Dawley rats. Following a 10-min intravenous infusion at 2.3 μmol/kg in PEG-400, the total body clearance of 40 is 5.2±0.82 mL/min/kg (means±SEM; n=3), indicating low clearance. The apparent terminal elimination half-life is 4.6±0.48 h. Oral administration of a PEG-400 suspension at 35 μmol/kg shows an oral bioavailability of 31% with prolonged absorption. BMS 433796 has satisfactory metabolic stability in human liver microsomal preparations and is not an inhibitor of human CYPs (IC₅₀>100 μM)^[1]. Brain Aβ40 is reduced as a result of administering BMS-433796 in a dose-dependent manner, with ED₅₀ value of 2.4 mg/kg, respectively^[2].