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000284027 041__ $$aEnglish
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000284027 1001_ $$0P:(DE-2719)9000794$$aTschirner, Sarah K$$b0$$eFirst author$$udzne
000284027 245__ $$aElenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.
000284027 260__ $$aWeinheim$$bWiley VCH$$c2026
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000284027 520__ $$aThe β-secretase BACE1 (β-site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co-inhibition of the BACE1-homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM-1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non-human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM-1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF.
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000284027 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000284027 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases
000284027 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBACE1 protein, human
000284027 650_7 $$2NLM Chemicals$$aBiomarkers
000284027 650_7 $$2NLM Chemicals$$aVascular Cell Adhesion Molecule-1
000284027 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: antagonists & inhibitors
000284027 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: cerebrospinal fluid
000284027 650_2 $$2MeSH$$aAnimals
000284027 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: antagonists & inhibitors
000284027 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: cerebrospinal fluid
000284027 650_2 $$2MeSH$$aMale
000284027 650_2 $$2MeSH$$aHumans
000284027 650_2 $$2MeSH$$aBiomarkers: cerebrospinal fluid
000284027 650_2 $$2MeSH$$aVascular Cell Adhesion Molecule-1: cerebrospinal fluid
000284027 650_2 $$2MeSH$$aMacaca fascicularis
000284027 7001_ $$0P:(DE-2719)2812225$$aSchmidt, Andree$$b1
000284027 7001_ $$aIto, Mana$$b2
000284027 7001_ $$aHyakkoku, Kana$$b3
000284027 7001_ $$aYoshimura, Akimasa$$b4
000284027 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b5$$udzne
000284027 7001_ $$aHoriguchi, Naotaka$$b6
000284027 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b7$$eLast author$$udzne
000284027 773__ $$0PERI:(DE-600)2037674-1$$a10.1002/pmic.70082$$gVol. 26, no. 1, p. 100 - 107$$n1$$p100 - 107$$tProteomics$$v26$$x1615-9853$$y2026
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