In vivo characterization of Aβ(40) changes in brain and cerebrospinal fluid using the novel γ-secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the rat

Plaques in the parenchyma of the brain containing A beta peptides are one of the hallmarks of Alzheimer's disease. These A beta peptides are produced by the final proteolytic cleavage of the amyloid precursor protein by the intramembraneous aspartyl protease gamma-secretase. Thus, one approach to lowering levels of A beta has been via the inhibition of the gamma-secretase enzyme. Here, we report a novel, bioavailable gamma-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 A beta 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 A beta could be maintained for 24 h, and comparable temporal reductions in rat brain and CSF A beta(40) further suggested that these two pools of A beta are related. This relationship between the brain and CSF A beta 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 A beta levels. These results demonstrate that MRK-560 is an orally bioavailable gamma-secretase inhibitor with the ability to markedly reduce A beta peptide in the brain and CSF of the rat and confirm the utility of the rat for assessing the effects of gamma-secretase inhibitors on central nervous system A beta( 40) levels in vivo.