EVP-0015962

EVP-0015962 is an orally active, blood-brain barrier-permeable γ-secretase inhibitor with an IC₅₀ of 3.9 μM. EVP-0015962 alters γ-secretase-mediated cleavage of amyloid precursor protein, reduces Aβ₄₂ production and increases Aβ₃₈ production. EVP-0015962 reduces Aβ aggregates, amyloid plaques and inflammatory markers in the brains of mice, and improves their cognitive impairment. EVP-0015962 can be used for the research of Alzheimer's disease^[1]. In Vitro:EVP-0015962 (0.003-10 μM; 16-18 h) acts as a γ-secretase modulator in H4-APP₇₅₁ cells, potently decreasing Aβ₄₂ (IC₅₀ = 67 nM) and increasing Aβ₃₈ without altering total Aβ levels at non-cytotoxic concentrations^[1].
EVP-0015962 (0.01-30 μM; 24 h) modulates γ-secretase in rat primary neocortical cultures, decreasing Aβ₄₂ (IC₅₀ = 427 nM) and increasing Aβ₃₈ without reducing Aβ_1-ₓ levels or inducing cytotoxicity at active concentrations^[1].
EVP-0015962 (0.001-100 μM; 3 h) modulates γ-secretase in a cell-free reconstituted system, selectively lowering Aβ₄₂ (IC₅₀ = 3.9 μM) without inhibiting AICD production or altering Aβ₄₀ levels^[1]. In Vivo:EVP-0015962 (10-30 mg/kg; p.o.; single dose) significantly reduces brain Aβ₄₂ levels by 39% in 21-week-old male Tg2576 mice^[1].
EVP-0015962 (20-60 mg/kg/day; p.o.; continuous via food formulation; 50 weeks) is well-tolerated in male Tg2576 mice, reduces brain Aβ₄₂ levels by 53-89%, aggregated Aβ by 73% at the high dose, amyloid plaque burden, and reactive gliosis, with a dose-dependent trend in efficacy^[1].
EVP-0015962 (20-60 mg/kg/day; p.o.; continuous via food formulation; 11 weeks) reverses the contextual fear conditioning cognitive deficit in 30-33-week-old male Tg2576 mice^[1].
EVP-0015962 (30 mg/kg; p.o.; single dose) does not reverse the contextual fear conditioning cognitive deficit in 30-week-old male Tg2576 mice^[1].