BMS-869780

BMS-869780 is an orally active non-acidic γ-secretase (γ-secretase) modulator. BMS-869780 regulates the activity of γ-secretase, thereby altering the production profile of β-amyloid proteins. When acting alone, it changes the relative levels of specific β-amyloid subtypes without inhibiting the total production of β-amyloid proteins. BMS-869780 exerts a synergistic effect with γ-secretase modulators of the acidic structural class to inhibit the total production of β-amyloid proteins in cell cultures^[1]. In Vitro:BMS-869780 alone does not inhibit the production of total Aβ, but when combined with acidic GSMs (GSM-2 or GSM-1 (HY-119165)) in human glioma H4-APPsw cells, it exhibits strong synergistic inhibitory effects on the production of Aβ1-x and Aβ1-40 (with combination index values as low as 0.05-0.06), and can induce the accumulation of α-CTF^[1]. In Vivo:BMS-869780 (25 mg/kg; p.o.; single dose) produces a significant reduction in brain Aβ_1-42 levels at 3 and 6 hours post-dose in wild-type C57Bl/6 mice, with no significant effect on total brain Aβ_1-x levels^[1].