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NEUROPHARMACOLOGY

Quantitative Measurement of Changes in Amyloid-(40) in the Rat Brain and Cerebrospinal Fluid following Treatment with the -Secretase Inhibitor LY-411575 [N²-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N¹-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]

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

The efficacy of -secretase inhibitors in vivo has, to date, been generally assessed in transgenic mouse models expressing increased levels of amyloid- (A) peptide thereby allowing the detection of changes in A production. However, it is not clear whether the in vivo potency of -secretase inhibitors is independent of the level of amyloid precursor protein expression. In other words, does a -secretase inhibitor have the same effect in nontransgenic physiological animals versus transgenic overexpressing animals? In the present study, an immunoassay has been developed which can detect A(40) in the rat brain, where concentrations are much lower than those seen in transgenic mice such as Tg2576 (c. 0.7 and 25 nM, respectively) and in cerebrospinal fluid (CSF, c. 0.3 nM). Using this immunoassay, the effects of the -secretase inhibitor LY-411575 [N²-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N¹-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide] were assessed and robust dose-dependent reductions in rat brain and CSF A(40) levels were observed with ID₅₀ values of 1.3 mg/kg for both brain and CSF. These values were comparable with those calculated for LY-411575 in transgenic mice. Time course experiments using LY-411575 demonstrated comparable temporal reductions in rat brain and CSF A(40), further suggesting these two pools of A are related. Accordingly, when all the data for the dose-response curve and time course were correlated, a strong association was observed between the brain and CSF A(40) levels. These data demonstrate the utility of the rat as a novel approach for assessing the effects of -secretase inhibitors on central nervous system A(40) levels in vivo.

Address correspondence to: Jonathan Best, Department of In Vivo Neuroscience, The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex, CM20 2QR, UK. E-mail: jonathan_best{at}merck.com

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