JNJ-40418677

JNJ-40418677 is an orally active modulator of γ-secretase, can cross the blood-brain barrier. JNJ-40418677 inhibits Aβ42 and NS2B-NS3 protease, with IC₅₀s of 200 nM and 3.9 μM, respectively. JNJ-40418677 displays good biological tolerance, can be use for Alzheimer’s disease research^[1][2][3]. IC50 & Target: IC50: 185 nM (rat Aβ42)^[1]; 200 nM (human Aβ42)^[2]; 3.9 μM (ZIKV NS2B-NS3 protease)^[3] In Vitro: JNJ-40418677 (0.2 nM-0.3 mM; 16 h) selectively reduces Aβ42 secretion in cell culture supernatants of human neuroblastoma cells with mean IC₅₀ of 200 nM and (0.2 nM-0.3 mM; 48 h) of rat primary neurons with mean IC₅₀ of 185 nM^[1].
JNJ-40418677 (10 μM, 100 μM; 18 h) does not inhibit Notch processing or (6 nM-20 μM; 18 h) not affect formation of other amyloid precursor protein cleavage (CTF-β, CTF-α) products, and shows no inhibitory activity against COX-1/2 at a high concentration of 60 μM^[1].
JNJ-40418677 suppresses ZIKV in human neuronal stem cells with an EC₅₀ value of 3.2 μM, and inhibits ZIKV NS2B-NS3 protease with an IC₅₀ value of 3.9 μM^[3]. In Vivo: JNJ-40418677 (10-300 mg/kg; p.o.) decreases Aβ42 brain levels in a dose-dependent manner 4 h after treatment, while increasing Aβ38 level in non-transgenic mouse brain^[1].
JNJ-40418677 (30 mg/kg; p.o.; once) shows the mean brain and plasma levels 4 h after single dose are both 17 μM, indicating good brain penetration in non-transgenic mouse brain^[1].
JNJ-40418677 (20-120 mg/kg; p.o.; 7 months) has good biological tolerance with no adverse effects in a chronic treatment in Tg2576 mice^[1].
JNJ-40418677 (20-120 mg/kg; p.o.; 7 months) decreases the plaque number and the area occupied by plaques in Tg2576 mice dose-dependently^[1].