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Optimization of 1,4-Oxazine β‑Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate

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journal contribution
posted on 29.05.2018, 00:00 by Harrie J. M. Gijsen, Sergio A. Alonso de Diego, Michel De Cleyn, Aránzazu García-Molina, Gregor J. Macdonald, Carolina Martínez-Lamenca, Daniel Oehlrich, Hana Prokopcova, Frederik J. R. Rombouts, Michel Surkyn, Andrés A. Trabanco, Sven Van Brandt, Dries Van den Bossche, Michiel Van Gool, Nigel Austin, Herman Borghys, Deborah Dhuyvetter, Diederik Moechars
In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the pKa of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aβ levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF3-group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.