Optimization of 1,4-Oxazine ß-Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate.
J Med Chem
; 61(12): 5292-5303, 2018 06 28.
Article
em En
| MEDLINE
| ID: mdl-29809004
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 Aß 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
/
Ácido Aspártico Endopeptidases
/
Secretases da Proteína Precursora do Amiloide
Tipo de estudo:
Etiology_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article