Chronic treatment with a novel gamma-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer’s disease

In this study the authors describe the characterization of a novel, NSAID-derived, orally active GSM, 2-(S)-(3,5-bis(4-(trifluoromethyl) phenyl)phenyl)-4-methylpentanoic acid (JNJ-40418677), with a strong potency towards Abeta42 inhibition and excellent brain penetration in mice.  The data showed that JNJ-40418677 selectively reduced Abeta 42 secretion in human neuroblastoma cells and rat primary neurons, but it did not inhibit Notch processing or formation of other amyloid precursor protein cleavage products. Oral treatment of non-transgenic mice with JNJ-40418677 resulted in an excellent brain penetration of the compound and a dose- and time-dependent decrease of brain Abeta42 levels. Chronic treatment of Tg2576 mice with JNJ-40418677 reduced brain Abeta levels, the area occupied by plaques and plaque number in a dose-dependent manner compared with transgenic vehicle-treated mice. The authors conclude that this compound therefore warrants further in vitro and in vivo investigation to explore its potential as a safe and effective disease-modifying treatment for AD.