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NEUROPHARMACOLOGY

P-Glycoprotein Efflux and Other Factors Limit Brain Amyloid β Reduction by β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitors in Mice

Research and Development, Bristol-Myers Squibb Co., Wallingford, Connecticut (J.E.Me., L.A.T., J.H.T., L.M., D.M.B., A.L., V.G., C.B., L.I., C.P., J.Ca., M.F., D.D., T.F., K.A.L., J.E.G., J.K., J.Co., M.P., K.J., R.E.O., J.E.Ma., C.F.A.); and Research and Development, Bristol-Myers Squibb Co., Hopewell, New Jersey (J.M., L.K., Y.K.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid β (Aβ) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from AD patients, genetic analysis of mutations that cause early onset forms of AD, and preclinical studies. Based on this hypothesis, β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors are an attractive therapeutic approach for AD because cleavage of the APP by BACE1 is required to form Aβ. In this study, three potent BACE1 inhibitors are characterized. All three inhibitors decrease Aβ formation in cultured cells with IC₅₀ values less than 10 nM. Analysis of APP C-terminal fragments by immunoblotting and Aβ peptides by mass spectrometry showed that these inhibitors decreased Aβ by inhibiting BACE1. An assay for Aβ1–40 in mice was developed and used to show that these BACE1 inhibitors decreased plasma Aβ1–40, but not brain Aβ1–40, in wild-type mice. Because these BACE1 inhibitors were substrates for P-glycoprotein (P-gp), a member of the ATP-binding cassette superfamily of efflux transporters, these inhibitors were administered to P-gp knockout (KO) mice. These studies showed that all three BACE1 inhibitors decreased brain Aβ1–40 in P-gp KO mice, demonstrating that P-gp is a major limitation for development of BACE1 inhibitors to test the amyloid hypothesis. A comparison of plasma Aβ1–40 and brain Aβ1–40 dose responses for these three compounds revealed differences in relative ED₅₀ values, indicating that factors other than P-gp can also contribute to poor brain activity by BACE1 inhibitors.

Address correspondence to: Dr. Jere E. Meredith Jr., Bristol Myers Squibb, 5 Research Parkway, Wallingford, CT. E-mail: jere.meredith{at}bms.com