JNJ-40418677

• CAT Number: R067040
• CAS Number: 1146594-87-7
• Molecular Formula: C26H22F6O2
• Molecular Weight: 480.44
• Purity: ≥95%
• Synonyms: (2S)-2-[3,5-bis[4-(trifluoromethyl)phenyl]phenyl]-4-methylpentanoic acid
• InChI: InChI=1S/C26H22F6O2/c1-15(2)11-23(24(33)34)20-13-18(16-3-7-21(8-4-16)25(27,28)29)12-19(14-20)17-5-9-22(10-6-17)26(30,31)32/h3-10,12-15,23H,11H2,1-2H3,(H,33,34)/t23-/m0/s1
• InChIKey: RQOWDDLKGBMJFX-QHCPKHFHSA-N
• SMILES: CC(C)CC(C1=CC(=CC(=C1)C2=CC=C(C=C2)C(F)(F)F)C3=CC=C(C=C3)C(F)(F)F)C(=O)O

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].
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].
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].

Reference

[1]. Van Broeck B, et al. Chronic treatment with a novel γ-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer’s disease. Br J Pharmacol. 2011 May;163(2):375-89.
 [Content Brief]

[2]. Harrie J.M. Gijsen, et al. Chapter Five – Secretase Inhibitors and Modulators as a Disease-Modifying Approach Against Alzheimer’s Disease. Annu Rep Med Chem. 2012. 47:55-69.

[3]. Samrat SK, et al. Antiviral Agents against Flavivirus Protease: Prospect and Future Direction. Pathogens. 2022 Feb 25;11(3):293.
 [Content Brief]