ELN 318463

ELN 318463 is an amyloid precursor protein (APP) selective γ-secretase inhibitor. ELN 318463 shows differential inhibition of presenilin (PS1)- and PS2-comprised γ-secretase with EC50s of 12 nM and 656 nM for PS1 and PS2, respectively. ELN 318463 is 51-fold more selective for PS1[1][2].

Research Areas >> Neurological Disease

EC50: 12 nM (PS1 γ-secretase), 656 nM (PS2 γ-secretase)[1]

ELN 318463 behaves as a classic γ-secretase inhibitor, demonstrates 75- to 120-fold selectivity for inhibiting Aβ production compared with Notch signaling in cells, and displaces an active site directed inhibitor at very high concentrations only in the presence of substrate[2].

ELN318463 (30 mg/kg or 100 mg/kg; orally) leads acute reduction of brain Aβ in in the PDAPP transgene model of Alzheimer's disease (AD) as well as in wild-type FVB strain mice[2]. Animal Model: Female, two- to three-month old, FVB/N mice and PDAPP transgene model of Alzheimer's disease (AD)[2] Dosage: 30 mg/kg or 100 mg/kg Administration: Orally Result: Brain levels at 30 mg/kg were 0.754 μM in FVB brains and 0.69 μM in PDAPP brains, and at 100 mg/kg dose the levels were 2.7 μM in FVB brains and 1.87 μM in PDAPP brains.

[1]. Zhao B, et al. Identification of gamma-secretase inhibitor potency determinants on presenilin. J Biol Chem. 2008 Feb 1;283(5):2927-38.

[2]. Basi GS, et al. Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease. Alzheimers Res Ther. 2010 Dec 29;2(6):36.