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NEUROPHARMACOLOGY

Dynamics of -Amyloid Reductions in Brain, Cerebrospinal Fluid, and Plasma of -Amyloid Precursor Protein Transgenic Mice Treated with a -Secretase Inhibitor

Bristol-Myers Squibb, Wallingford, Connecticut (D.M.B., V.L.G., J.A.C., A.L., S.B.H., M.Z., B.J.R., C.T.P., J.W., S.B.R., J.P.H., J.K.L., R.D., T.A.V., D.W.S., K.M.F.); Vertex Pharmaceuticals, Cambridge, Massachusetts (A.L.); SIBIA Neurosciences, Inc., La Jolla, California (B.M., B.W., J.J.A.); Merck Research Laboratories, San Diego, California (B.M., B.W.); Neurogenetics Inc., La Jolla, California (K.S.); IntraCellular Therapies, New York, New York (J.P.H.); Cypress Bioscience, Inc., San Diego, California (J.J.A.); Pfizer, Groton, Connecticut (J.K.L.); Algos Therapeutics, Inc., St. Paul, Minnesota (T.A.V.); and Johnson and Johnson PRD, Spring House, Pennsylvania (K.M.F.)

-Secretase inhibitors are one promising approach to the development of a therapeutic for Alzheimer's disease (AD). -Secretase inhibitors reduce brain -amyloid peptide (A), which is believed to be a major contributor in the etiology of AD. Transgenic mice overexpressing the human -amyloid precursor protein (APP) are valuable models to examine the dynamics of A changes with -secretase inhibitors in plaque-free and plaque-bearing animals. BMS-299897 2-[(1R)-1-[[(4-chlorophenyl)sulfony](2,5-difluorophenyl)amino]ethyl]-5-fluorobenzenepropanoic acid, a -secretase inhibitor, showed dose- and time dependent reductions of A in brain, cerebrospinal fluid (CSF), and plasma in young transgenic mice, with a significant correlation between brain and CSF A levels. Because CSF and brain interstitial fluid are distinct compartments in composition and location, this correlation could not be assumed. In contrast, aged transgenic mice with large accumulations of A in plaques showed reductions in CSF A in the absence of measurable changes in plaque A in the brain after up to 2 weeks of treatment. Hence, CSF A levels were a valuable measure of -secretase activity in the central nervous system in either the presence or absence of plaques. Transgenic mice were also used to examine potential side effects due to Notch inhibition. BMS-299897 was 15-fold more effective at preventing the cleavage of APP than of Notch in vitro. No changes in the maturation of CD8+ thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897, showing that it is possible for -secretase inhibitors to reduce brain A without causing Notch-mediated toxicity.

Address correspondence to: Dr. Donna M. Barten, Neuroscience Drug Discovery, Bristol-Myers Squibb, P.O. Box 5100, 3CD-405, 5 Research Pkwy., Wallingford, CT 06492. E-mail: donna.barten{at}bms.com

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