title: Robust Translation of γ-Secretase Modulator Pharmacology across Preclinical Species and Human Subjects.
abstract: The amyloid-β peptide (Aβ)-in particular, the 42-amino acid form, Aβ1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, β-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Toyn
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boy
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Joseph
authors.initials: J
authors.lastname: Raybon
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Alan S
authors.initials: AS
authors.lastname: Robertson
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Valerie
authors.initials: V
authors.lastname: Guss
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Nina
authors.initials: N
authors.lastname: Hoque
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Francis
authors.initials: F
authors.lastname: Sweeney
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Zhuo
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Wendy
authors.initials: W
authors.lastname: Clarke
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Kimberly
authors.initials: K
authors.lastname: Snow
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: R Rex
authors.initials: RR
authors.lastname: Denton
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Dmitry
authors.initials: D
authors.lastname: Zuev
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Thompson
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: John
authors.initials: J
authors.lastname: Morrison
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: James
authors.initials: J
authors.lastname: Grace
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Flora
authors.initials: F
authors.lastname: Berisha
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Michael
authors.initials: M
authors.lastname: Furlong
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Lentz
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Ramesh
authors.initials: R
authors.lastname: Padmanabha
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Lynda
authors.initials: L
authors.lastname: Cook
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Cong
authors.initials: C
authors.lastname: Wei
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Dieter M
authors.initials: DM
authors.lastname: Drexler
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Charlie F
authors.initials: CF
authors.lastname: Albright
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Maciej
authors.initials: M
authors.lastname: Gasior
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Holly D
authors.initials: HD
authors.lastname: Soares
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
authors.forename: Malaz
authors.initials: M
authors.lastname: AbuTarif
authors.affiliation: Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.) Michael.ahlijanian@bms.com.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Ahlijanian
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000235:genetics; D000814:Aniline Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000378:metabolism; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: C000619244:7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta(d)pyrimidine-2,4-diamine; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; C000619245:BMS-986133; D001952:Bridged-Ring Compounds; D011743:Pyrimidines; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases