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NEUROPHARMACOLOGY

In Vivo Characterization of A(40) Changes in Brain and Cerebrospinal Fluid Using the Novel -Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the Rat

Departments of In Vivo Neuroscience (J.D.B., M.T.J., F.O., J.R.A.), Medicinal Chemistry (I.C., T.H.), Drug Metabolism and Pharmacokinetics (M.R., P.M.-G., C.P.), and Molecular and Cellular Neuroscience (M.S.S.), The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex, United Kingdom

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

Address correspondence to: Dr. Mark Shearman, Merck Research Laboratories, 33, Avenue Louis Pasteur, Boston, MA 02115. E-mail: mark_shearman{at}merck.com

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