The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia a...

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Published inThe Journal of neuroscience Vol. 35; no. 3; pp. 1199 - 1210
Main Authors May, Patrick C, Willis, Brian A, Lowe, Stephen L, Dean, Robert A, Monk, Scott A, Cocke, Patrick J, Audia, James E, Boggs, Leonard N, Borders, Anthony R, Brier, Richard A, Calligaro, David O, Day, Theresa A, Ereshefsky, Larry, Erickson, Jon A, Gevorkyan, Hykop, Gonzales, Celedon R, James, Douglas E, Jhee, Stanford S, Komjathy, Steven F, Li, Linglin, Lindstrom, Terry D, Mathes, Brian M, Martényi, Ferenc, Sheehan, Scott M, Stout, Stephanie L, Timm, David E, Vaught, Grant M, Watson, Brian M, Winneroski, Leonard L, Yang, Zhixiang, Mergott, Dustin J
Format Journal Article
LanguageEnglish
Published United States Society for Neuroscience 21.01.2015
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Abstract BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
AbstractList BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
BACE1 is a key protease controlling the formation of amyloid beta , a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid beta lowering in nonclinical animal models. Similar potent and persistent amyloid beta lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
Author Jhee, Stanford S
Mathes, Brian M
Sheehan, Scott M
Winneroski, Leonard L
Vaught, Grant M
Ereshefsky, Larry
Audia, James E
Lowe, Stephen L
Yang, Zhixiang
Dean, Robert A
Gevorkyan, Hykop
Komjathy, Steven F
Calligaro, David O
Day, Theresa A
Watson, Brian M
Borders, Anthony R
Erickson, Jon A
James, Douglas E
Lindstrom, Terry D
Stout, Stephanie L
Martényi, Ferenc
Cocke, Patrick J
Timm, David E
Boggs, Leonard N
Brier, Richard A
Li, Linglin
May, Patrick C
Willis, Brian A
Monk, Scott A
Mergott, Dustin J
Gonzales, Celedon R
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Issue 3
Keywords BACE1
clinical trial
nonclinical animal model
Alzheimer's disease
amyloid beta
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Author contributions: P.C.M., B. Willis, S.L., R.D., J.A., D.C., J.E., F.M., G.V., B. Watson, L.W., and D.M. designed research; P.C.M., B. Willis, R.D., S.M., L.B., A.B., R.B., T.D., L.E., H.G., S.J., L.L., S. Stout, D.E.T., Z.Y., and D.M. performed research; S.M. contributed unpublished reagents/analytic tools; P.C.M., B. Willis, S.L., R.D., S.M., P.C., J.A., L.B., A.B., R.B., D.C., L.E., H.G., C.G., D.J., S.J., S.K., L.L., T.L., B.M., F.M., S. Sheehan, S. Stout, D.E.T., G.V., B. Watson, L.W., Z.Y., and D.M. analyzed data; P.C.M., B. Willis, S.L., R.D., S.M., P.C., J.A., L.B., A.B., R.B., D.C., T.D., L.E., J.E., H.G., C.G., D.J., S.J., S.K., L.L., T.L., B.M., F.M., S. Sheehan, S. Stout, D.E.T., G.V., B. Watson, L.W., Z.Y., and D.M. wrote the paper.
F. Martényi's present address: Takeda Pharmaceuticals, Deerfield, IL 60015.
J.E. Audia's present address: Constellation Pharmaceuticals, Cambridge, MA 02142.
Retired (formerly Professor of Psychiatry, Pharmacology, and Pharmacy at The University of Texas at Austin, 78705).
ORCID 0000-0002-7096-7992
0000-0003-1802-0758
0000-0003-2501-8138
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Snippet BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease...
BACE1 is a key protease controlling the formation of amyloid beta , a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's...
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SubjectTerms Alzheimer Disease - drug therapy
Amyloid beta-Peptides - blood
Amyloid beta-Peptides - cerebrospinal fluid
Amyloid beta-Peptides - metabolism
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Animals
Aspartic Acid Endopeptidases - antagonists & inhibitors
Disease Models, Animal
Dogs
Heterocyclic Compounds, 2-Ring - pharmacokinetics
Heterocyclic Compounds, 2-Ring - pharmacology
Heterocyclic Compounds, 2-Ring - therapeutic use
Humans
Mice
Picolinic Acids - pharmacokinetics
Picolinic Acids - pharmacology
Picolinic Acids - therapeutic use
Protease Inhibitors - pharmacokinetics
Protease Inhibitors - pharmacology
Protease Inhibitors - therapeutic use
Title The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans
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Volume 35
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