Itanapraced (CHF5074)

CHF5074 is a modulator of γ-secretase and a derivative of flurbiprofen .¹ It inhibits the secretion of amyloid β (1-42) (Aβ42) in H4-APP695NL human neuroglioma cells that overexpress a mutated form of amyloid precursor protein (APP; IC₅₀ = 41 ?M) and selectively inhibits secretion of Aβ42 over Aβ40 with 79% and 14% inhibition, respectively, at 100 ?M. It does not inhibit COX-1 or COX-2 when used at concentrations up to 100 and 500 ?M, respectively, and does not induce Notch cleavage in HEK293 cells expressing the APP mutant APPswe at 5 ?M.^1,2 CHF5074 decreases plasma levels of Aβ42 in the Tg2576 transgenic mouse model of Alzheimer’s disease when administered at a dose of 12.5 mg/kg per day for seven days and reduces the plaque area and number of plaques in the brain of hAPP mice when administered in the diet at 375 ppm for six months.^1,3 It decreases the distance traveled, but not the escape latency, in the Morris water maze in hAPP mice compared to hAPP animals administered a vehicle control.

1.Peretto, I., Radaelli, S., Parini, C., et al.Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of β-amyloid1-42 secretionJ. Med. Chem.48(18)5705-5720(2005) 2.Imbimbo, B.P., Del Giudice, E., Colavito, D., et al.1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel γ-secretase modulator, reduces brain β-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicityJ. Pharmacol. Exp. Ther.323(3)822-830(2007) 3.Imbimbo, B.P., Hutter-Paier, B., Villetti, G., et al.CHF5074, a novel γ-secretase modulator, attenuates brain β-amyloid pathology and learning deficit in a mouse model of Alzheimer's diseaseBr. J. Pharmac.156(6)982-993(2009)