| Literature DB >> 29809004 |
Harrie J M Gijsen1, Sergio A Alonso de Diego2, Michel De Cleyn1, Aránzazu García-Molina2, Gregor J Macdonald1, Carolina Martínez-Lamenca1, Daniel Oehlrich1, Hana Prokopcova1, Frederik J R Rombouts1, Michel Surkyn1, Andrés A Trabanco2, Sven Van Brandt1, Dries Van den Bossche1, Michiel Van Gool2, Nigel Austin3, Herman Borghys3, Deborah Dhuyvetter3, Diederik Moechars4.
Abstract
In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p Ka 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.Entities:
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Year: 2018 PMID： 29809004 DOI： 10.1021/acs.jmedchem.8b00304
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446