Abstract

Plaques in the parenchyma of the brain containing Aβ peptides are one of the hallmarks of Alzheimer's disease. These Aβ peptides are produced by the final proteolytic cleavage of the amyloid precursor protein by the intramembraneous aspartyl protease γ-secretase. Thus, one approach to lowering levels of Aβ has been via the inhibition of the γ-secretase enzyme. Here, we report a novel, bioavailable γ-secretase inhibitor, N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) that displayed oral pharmacokinetics suitable for once-a-day dosing. It was able to markedly reduce Aβ in the brain and cerebrospinal fluid (CSF) in the rat, with ED₅₀ values of 6 and 10 mg/kg, respectively. Time-course experiments using MRK-560 demonstrated these reductions in Aβ could be maintained for 24 h, and comparable temporal reductions in rat brain and CSF Aβ(40) further suggested that these two pools of Aβ are related. This relationship between the brain and CSF Aβ was maintained when MRK-560 was dosed once a day for 2 weeks, and accordingly, when all the data for the dose-response curve and time courses were correlated, a strong association was observed between the brain and CSF Aβ levels. These results demonstrate that MRK-560 is an orally bioavailable γ-secretase inhibitor with the ability to markedly reduce Aβ peptide in the brain and CSF of the rat and confirm the utility of the rat for assessing the effects of γ-secretase inhibitors on central nervous system Aβ(40) levels in vivo.