Home > In process > Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates. > print

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024 7 _ |a 10.1002/pmic.70082
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037 _ _ |a DZNE-2026-00070
041 _ _ |a English
082 _ _ |a 540
100 1 _ |a Tschirner, Sarah K
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245 _ _ |a Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.
260 _ _ |a Weinheim
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520 _ _ |a The β-secretase BACE1 (β-site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co-inhibition of the BACE1-homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM-1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non-human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM-1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF.
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650 _ 7 |a Amyloid Precursor Protein Secretases
|0 EC 3.4.-
|2 NLM Chemicals
650 _ 7 |a Aspartic Acid Endopeptidases
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650 _ 7 |a BACE1 protein, human
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650 _ 7 |a Biomarkers
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650 _ 7 |a Vascular Cell Adhesion Molecule-1
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650 _ 2 |a Amyloid Precursor Protein Secretases: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Biomarkers: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Vascular Cell Adhesion Molecule-1: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Macaca fascicularis
|2 MeSH
700 1 _ |a Schmidt, Andree
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700 1 _ |a Ito, Mana
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700 1 _ |a Hyakkoku, Kana
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700 1 _ |a Yoshimura, Akimasa
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700 1 _ |a Müller, Stephan A
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700 1 _ |a Horiguchi, Naotaka
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700 1 _ |a Lichtenthaler, Stefan F
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773 _ _ |a 10.1002/pmic.70082
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