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Research ArticleNeuropharmacology

Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat

Charles F. Albright, Randy C. Dockens, Jere E. Meredith Jr., Richard E. Olson, Randy Slemmon, Kimberley A. Lentz, Jun-Sheng Wang, R. Rex Denton, Gary Pilcher, Paul W. Rhyne, Joseph J. Raybon, Donna M. Barten, Catherine Burton, Jeremy H. Toyn, Sethu Sankaranarayanan, Craig Polson, Valerie Guss, Randy White, Frank Simutis, Thomas Sanderson, Kevin W. Gillman, John E. Starrett Jr., Joanne Bronson, Oleksandr Sverdlov, Shu-Pang Huang, Lorna Castaneda, Howard Feldman, Vlad Coric, Robert Zaczek, John E. Macor, John Houston, Robert M. Berman and Gary Tong
Journal of Pharmacology and Experimental Therapeutics March 2013, 344 (3) 686-695; DOI: https://doi.org/10.1124/jpet.112.199356
Charles F. Albright
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Randy C. Dockens
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Jere E. Meredith Jr.
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Richard E. Olson
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Randy Slemmon
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Kimberley A. Lentz
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Jun-Sheng Wang
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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R. Rex Denton
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Gary Pilcher
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Paul W. Rhyne
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Joseph J. Raybon
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Donna M. Barten
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Catherine Burton
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Jeremy H. Toyn
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Sethu Sankaranarayanan
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Craig Polson
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Valerie Guss
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Randy White
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Frank Simutis
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Thomas Sanderson
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Kevin W. Gillman
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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John E. Starrett Jr.
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Joanne Bronson
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Oleksandr Sverdlov
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Shu-Pang Huang
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Lorna Castaneda
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Howard Feldman
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Vlad Coric
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Robert Zaczek
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John E. Macor
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John Houston
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Gary Tong
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut (C.F.A., J.E.M., R.E.O., K.A.L., R.R.D., G.P., J.J.R., D.M.B., C.B., J.H.T., S.S., C.P., V.G., K.W.G., J.E.S., J.B., H.F., V.C., R.Z., J.E.M., J.H., R.M.B.); Research and Development, Bristol-Myers Squibb, Hopewell Facility, Pennington, New Jersey (R.D., R.S., G.T.); Research and Development, Bristol-Myers Squibb, Lawrenceville, New Jersey (J.-S.W., P.W.R., O.S., S.-P.H., L.C.); and Research and Development, Bristol-Myers Squibb, Department of Drug Safety Evaluation, Mount Vernon Facility, Evansville, Indiana (R.W., F.S., T.S.)
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Abstract

A hallmark of Alzheimer’s disease (AD) pathology is the accumulation of brain amyloid β-peptide (Aβ), generated by γ-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, γ-secretase inhibitors (GSIs) may lower brain Aβ and offer a potential new approach to treat AD. As γ-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of Aβ and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) Aβ levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF Aβ40 and Aβ42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending–dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF Aβ40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF Aβ levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.

Footnotes

  • This work was funded by Bristol-Myers Squibb. Editorial and writing assistance was provided by StemScientific and Oxford PharmaGenesis and was funded by Bristol-Myers Squibb. All of the authors were employees of Bristol-Myers Squibb at the time when this work was done; many of the authors own in excess of $10,000 of company stock. Additionally, some authors are inventors on patents related to the subject matter.

  • dx.doi.org/10.1124/jpet.112.199356.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Received September 20, 2012.
  • Accepted December 27, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 3
1 Mar 2013
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Research ArticleNeuropharmacology

Pharmacodynamics of γ-Secretase Inhibition by Avagacestat

Charles F. Albright, Randy C. Dockens, Jere E. Meredith, Richard E. Olson, Randy Slemmon, Kimberley A. Lentz, Jun-Sheng Wang, R. Rex Denton, Gary Pilcher, Paul W. Rhyne, Joseph J. Raybon, Donna M. Barten, Catherine Burton, Jeremy H. Toyn, Sethu Sankaranarayanan, Craig Polson, Valerie Guss, Randy White, Frank Simutis, Thomas Sanderson, Kevin W. Gillman, John E. Starrett, Joanne Bronson, Oleksandr Sverdlov, Shu-Pang Huang, Lorna Castaneda, Howard Feldman, Vlad Coric, Robert Zaczek, John E. Macor, John Houston, Robert M. Berman and Gary Tong
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 686-695; DOI: https://doi.org/10.1124/jpet.112.199356

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Research ArticleNeuropharmacology

Pharmacodynamics of γ-Secretase Inhibition by Avagacestat

Charles F. Albright, Randy C. Dockens, Jere E. Meredith, Richard E. Olson, Randy Slemmon, Kimberley A. Lentz, Jun-Sheng Wang, R. Rex Denton, Gary Pilcher, Paul W. Rhyne, Joseph J. Raybon, Donna M. Barten, Catherine Burton, Jeremy H. Toyn, Sethu Sankaranarayanan, Craig Polson, Valerie Guss, Randy White, Frank Simutis, Thomas Sanderson, Kevin W. Gillman, John E. Starrett, Joanne Bronson, Oleksandr Sverdlov, Shu-Pang Huang, Lorna Castaneda, Howard Feldman, Vlad Coric, Robert Zaczek, John E. Macor, John Houston, Robert M. Berman and Gary Tong
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 686-695; DOI: https://doi.org/10.1124/jpet.112.199356
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