Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for...

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Published inThe Journal of neuroscience Vol. 31; no. 46; pp. 16507 - 16516
Main Authors May, Patrick C, Dean, Robert A, Lowe, Stephen L, Martenyi, Ferenc, Sheehan, Scott M, Boggs, Leonard N, Monk, Scott A, Mathes, Brian M, Mergott, Dustin J, Watson, Brian M, Stout, Stephanie L, Timm, David E, Smith Labell, Elizabeth, Gonzales, Celedon R, Nakano, Masako, Jhee, Stanford S, Yen, Mark, Ereshefsky, Larry, Lindstrom, Terry D, Calligaro, David O, Cocke, Patrick J, Greg Hall, D, Friedrich, Stuart, Citron, Martin, Audia, James E
Format Journal Article
LanguageEnglish
Published United States Society for Neuroscience 16.11.2011
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Abstract According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.
AbstractList According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [( S )-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4 H -[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.
According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.
Author Jhee, Stanford S
Mathes, Brian M
Sheehan, Scott M
Greg Hall, D
Nakano, Masako
Ereshefsky, Larry
Audia, James E
Martenyi, Ferenc
Lowe, Stephen L
Smith Labell, Elizabeth
Friedrich, Stuart
Dean, Robert A
Watson, Brian M
Calligaro, David O
Yen, Mark
Lindstrom, Terry D
Stout, Stephanie L
Cocke, Patrick J
Timm, David E
Boggs, Leonard N
May, Patrick C
Monk, Scott A
Mergott, Dustin J
Gonzales, Celedon R
Citron, Martin
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  organization: Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285, USA
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/22090477$$D View this record in MEDLINE/PubMed
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Cites_doi 10.1016/j.bmcl.2010.09.029
10.1038/990107
10.1126/science.1156609
10.1016/j.bmc.2008.12.067
10.1111/j.1471-4159.2006.04260.x
10.1073/pnas.94.4.1550
10.1212/01.wnl.0000256043.50901.e3
10.1046/j.1471-4159.2001.00012.x
10.1517/14728222.12.9.1191
10.1038/ncb1602
10.1523/JNEUROSCI.2766-05.2005
10.1107/S0907444910007493
10.1002/ddr.20289
10.1021/jo01038a035
10.1186/1750-1326-5-31
10.1016/S1359-6446(04)03069-7
10.1006/mcne.1999.0811
10.1002/jnr.10745
10.1096/fj.08-106666
10.1038/373523a0
10.1126/science.1095862
10.1126/science.1132341
10.1002/ana.21623
10.1038/85064
10.1038/990114
10.1124/jpet.108.138974
10.1126/science.1072994
10.1111/j.1471-4159.2004.02764.x
10.1124/jpet.107.130039
10.1073/pnas.97.4.1456
10.1038/85059
10.1038/360672a0
10.1107/S0907444994003112
10.1002/ana.410370303
10.1124/jpet.108.143628
10.1093/hmg/10.12.1317
10.1126/science.286.5440.735
10.1074/jbc.M414648200
10.1126/science.290.5489.150
10.1021/jm040031v
10.1038/nn1797
10.1074/jbc.M307228200
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Notes Author contributions: P.C.M., R.A.D., S.L.L., F.M., S.M.S., D.E.T., T.D.L., D.O.C., P.J.C., M.C., and J.E.A. designed research; S.L.L., S.M.S., L.N.B., S.A.M., B.M.M., D.J.M., B.M.W., S.L.S., D.E.T., E.S.L., C.R.G., M.N., S.S.J., M.Y., L.E., and D.G.H. performed research; P.C.M., R.A.D., S.L.L., F.M., S.M.S., L.N.B., S.A.M., B.M.M., D.J.M., B.M.W., S.L.S., D.E.T., E.S.L., C.R.G., M.N., S.S.J., M.Y., L.E., T.D.L., D.O.C., P.J.C., D.G.H., S.F., M.C., and J.E.A. analyzed data; P.C.M., R.A.D., P.J.C., M.C., and J.E.A. wrote the paper.
J. E. Audia's present address: Constellation Pharmaceuticals, Cambridge, MA 02142.
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References 2023041303534015000_31.46.16507.6
2023041303534015000_31.46.16507.7
2023041303534015000_31.46.16507.4
2023041303534015000_31.46.16507.5
2023041303534015000_31.46.16507.2
2023041303534015000_31.46.16507.31
2023041303534015000_31.46.16507.3
2023041303534015000_31.46.16507.10
2023041303534015000_31.46.16507.32
2023041303534015000_31.46.16507.1
2023041303534015000_31.46.16507.30
2023041303534015000_31.46.16507.13
2023041303534015000_31.46.16507.35
2023041303534015000_31.46.16507.14
2023041303534015000_31.46.16507.36
2023041303534015000_31.46.16507.11
2023041303534015000_31.46.16507.33
2023041303534015000_31.46.16507.12
2023041303534015000_31.46.16507.34
2023041303534015000_31.46.16507.17
2023041303534015000_31.46.16507.39
2023041303534015000_31.46.16507.18
2023041303534015000_31.46.16507.15
2023041303534015000_31.46.16507.37
2023041303534015000_31.46.16507.16
2023041303534015000_31.46.16507.38
2023041303534015000_31.46.16507.19
2023041303534015000_31.46.16507.8
2023041303534015000_31.46.16507.9
2023041303534015000_31.46.16507.20
2023041303534015000_31.46.16507.42
2023041303534015000_31.46.16507.21
2023041303534015000_31.46.16507.43
2023041303534015000_31.46.16507.40
2023041303534015000_31.46.16507.41
2023041303534015000_31.46.16507.24
2023041303534015000_31.46.16507.25
2023041303534015000_31.46.16507.22
2023041303534015000_31.46.16507.44
2023041303534015000_31.46.16507.23
2023041303534015000_31.46.16507.28
2023041303534015000_31.46.16507.29
2023041303534015000_31.46.16507.26
2023041303534015000_31.46.16507.27
References_xml – ident: 2023041303534015000_31.46.16507.25
  doi: 10.1016/j.bmcl.2010.09.029
– ident: 2023041303534015000_31.46.16507.41
  doi: 10.1038/990107
– ident: 2023041303534015000_31.46.16507.29
  doi: 10.1126/science.1156609
– ident: 2023041303534015000_31.46.16507.44
  doi: 10.1016/j.bmc.2008.12.067
– ident: 2023041303534015000_31.46.16507.19
  doi: 10.1111/j.1471-4159.2006.04260.x
– ident: 2023041303534015000_31.46.16507.20
  doi: 10.1073/pnas.94.4.1550
– ident: 2023041303534015000_31.46.16507.1
  doi: 10.1212/01.wnl.0000256043.50901.e3
– ident: 2023041303534015000_31.46.16507.7
  doi: 10.1046/j.1471-4159.2001.00012.x
– ident: 2023041303534015000_31.46.16507.3
  doi: 10.1517/14728222.12.9.1191
– ident: 2023041303534015000_31.46.16507.21
  doi: 10.1038/ncb1602
– ident: 2023041303534015000_31.46.16507.22
  doi: 10.1523/JNEUROSCI.2766-05.2005
– ident: 2023041303534015000_31.46.16507.8
  doi: 10.1107/S0907444910007493
– ident: 2023041303534015000_31.46.16507.36
  doi: 10.1002/ddr.20289
– ident: 2023041303534015000_31.46.16507.34
– ident: 2023041303534015000_31.46.16507.33
  doi: 10.1021/jo01038a035
– ident: 2023041303534015000_31.46.16507.13
  doi: 10.1186/1750-1326-5-31
– ident: 2023041303534015000_31.46.16507.15
  doi: 10.1016/S1359-6446(04)03069-7
– ident: 2023041303534015000_31.46.16507.18
  doi: 10.1006/mcne.1999.0811
– ident: 2023041303534015000_31.46.16507.10
  doi: 10.1002/jnr.10745
– ident: 2023041303534015000_31.46.16507.17
  doi: 10.1096/fj.08-106666
– ident: 2023041303534015000_31.46.16507.11
  doi: 10.1038/373523a0
– ident: 2023041303534015000_31.46.16507.27
  doi: 10.1126/science.1095862
– ident: 2023041303534015000_31.46.16507.39
  doi: 10.1126/science.1132341
– ident: 2023041303534015000_31.46.16507.2
  doi: 10.1002/ana.21623
– ident: 2023041303534015000_31.46.16507.4
  doi: 10.1038/85064
– ident: 2023041303534015000_31.46.16507.35
  doi: 10.1038/990114
– ident: 2023041303534015000_31.46.16507.26
  doi: 10.1124/jpet.108.138974
– ident: 2023041303534015000_31.46.16507.12
  doi: 10.1126/science.1072994
– ident: 2023041303534015000_31.46.16507.42
  doi: 10.1111/j.1471-4159.2004.02764.x
– ident: 2023041303534015000_31.46.16507.31
  doi: 10.1124/jpet.107.130039
– ident: 2023041303534015000_31.46.16507.23
  doi: 10.1073/pnas.97.4.1456
– ident: 2023041303534015000_31.46.16507.24
  doi: 10.1038/85059
– ident: 2023041303534015000_31.46.16507.5
  doi: 10.1038/360672a0
– ident: 2023041303534015000_31.46.16507.6
  doi: 10.1107/S0907444994003112
– ident: 2023041303534015000_31.46.16507.43
  doi: 10.1002/ana.410370303
– ident: 2023041303534015000_31.46.16507.32
  doi: 10.1124/jpet.108.143628
– ident: 2023041303534015000_31.46.16507.30
  doi: 10.1093/hmg/10.12.1317
– ident: 2023041303534015000_31.46.16507.38
  doi: 10.1126/science.286.5440.735
– ident: 2023041303534015000_31.46.16507.40
  doi: 10.1074/jbc.M414648200
– ident: 2023041303534015000_31.46.16507.14
  doi: 10.1126/science.290.5489.150
– ident: 2023041303534015000_31.46.16507.9
  doi: 10.1021/jm040031v
– ident: 2023041303534015000_31.46.16507.37
– ident: 2023041303534015000_31.46.16507.16
  doi: 10.1038/nn1797
– ident: 2023041303534015000_31.46.16507.28
  doi: 10.1074/jbc.M307228200
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Snippet According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation...
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StartPage 16507
SubjectTerms Adult
Alzheimer Disease - cerebrospinal fluid
Alzheimer Disease - drug therapy
Amyloid beta-Peptides - cerebrospinal fluid
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - cerebrospinal fluid
Amyloid beta-Protein Precursor - genetics
Amyloid Precursor Protein Secretases - analysis
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Analysis of Variance
Animals
Aspartic Acid Endopeptidases - analysis
Aspartic Acid Endopeptidases - antagonists & inhibitors
Cells, Cultured
Cerebral Cortex - cytology
Crystallography - methods
Disease Models, Animal
Dogs
Dose-Response Relationship, Drug
Embryo, Mammalian
Enzyme Inhibitors - blood
Enzyme Inhibitors - pharmacology
Enzyme-Linked Immunosorbent Assay - methods
Female
Humans
Male
Mice
Mice, Transgenic
Middle Aged
Models, Chemical
Mutation - genetics
Neurons - drug effects
Peptide Fragments - cerebrospinal fluid
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
Rats
Rats, Sprague-Dawley
Thiazines - pharmacology
Thiazines - therapeutic use
Time Factors
Young Adult
Title Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor
URI https://www.ncbi.nlm.nih.gov/pubmed/22090477
https://pubmed.ncbi.nlm.nih.gov/PMC6633289
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