1443035-49-1Relevant articles and documents
Optimization of 1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate
Gijsen, Harrie J. M.,Alonso De Diego, Sergio A.,De Cleyn, Michel,García-Molina, Aránzazu,Macdonald, Gregor J.,Martínez-Lamenca, Carolina,Oehlrich, Daniel,Prokopcova, Hana,Rombouts, Frederik J. R.,Surkyn, Michel,Trabanco, Andrés A.,Van Brandt, Sven,Van Den Bossche, Dries,Van Gool, Michiel,Austin, Nigel,Borghys, Herman,Dhuyvetter, Deborah,Moechars, Diederik
, p. 5292 - 5303 (2018/06/13)
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.