Diastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine ß-amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation.
Bioorg Med Chem Lett
; 28(6): 1111-1115, 2018 04 01.
Article
em En
| MEDLINE
| ID: mdl-29426770
ABSTRACT
The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC50 = 15â¯nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Aß40 levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Aza
/
Compostos Bicíclicos com Pontes
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Ácido Aspártico Endopeptidases
/
Inibidores Enzimáticos
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Secretases da Proteína Precursora do Amiloide
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article