AMG-8718

AMG-8718 is a potent, selective and orally active BACE1 inhibitor with IC₅₀ values of 0.0007, 0.005 µM for BACE1 and BACE2, respectively. AMG-8718 significantly decreases Aβ₄₀ levels in the CSF and brain^[1]. In Vitro: AMG-8718 (compound 42) shows good stability in human and rat liver microsomes, hERG binding activity with an K_i value of >10 µM^[1]. In Vivo: AMG-8718 (compound 42) (10 mg/kg; p.o.)shows significantly decreases Aβ₄₀ levels in the CSF and brain^[1].
AMG-8718 (i.v. for 2 mg/kg or p.o. for 5 mg/kg) shows good bioavailability of 70%, 96%,101% for rats, beagle dog, monkey, respectively^[1].
AMG-8718 (30 mg/kg for; p.o.) dose-dependent decreases in both CSF and brain Aβ levels at 4 h time points with 50% Aβ reduction (EC₅₀) values of 18 and 67 nM for CSF and brain respectively in rats^[1].
AMG-8718 (2.5, 8, 16 mg/kg; i.v.; a series of three 30 min infusions) shows high unbound plasma concentrations with 0.298, 1.70, 3.62 µM at the end of each infusion in chloralose-anesthetized dogs^[1].
Pharmacokinetic Parameters ofAMG-8718 in rats, beagle dog, cynomolgus monkey^[1].

species	Cl (L/h/kg)	Vdss(L/kg)	t1/2(h)	Cmax (µM)	tmax(h)	% F	plasma protein binding (Fu)
	i.v.			p.o.
rat	0.33	1.1	4.8	3.8	1.7	70	0.013
beagle dog	0.26	1.6	5.2	8.1	1.0	96	0.038
monkey	0.61	2.2	7.7	6.1	1.7	101	0.054

2 mg/kg i.v.; rats (DMSO), dog (1% Tween80/2% HMPC/97% water at pH = 4), cynomolgus monkey (25% HBC/75% water at pH = 4); 5 mg/kg p.o. (1% Tween80/2% HMPC/97% water at pH = 2)^[1].