Factor VIIa inhibitors: target hopping in the serine protease family using X-ray structure determination.
Bioorg Med Chem Lett
; 18(16): 4533-7, 2008 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-18674905
ABSTRACT
Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. Compound 1 was discovered from focused screening of serine protease-directed compounds from our internal collection. Using parallel synthesis supported by structure-based drug design, we identified peptidemimetic FVIIa/TF inhibitors (compounds 4-11) containing L-Gln or L-Met as the P2 moiety. However, these compounds lacked the selectivity of other serine proteases in the coagulation cascade, especially thrombin. Further optimization of these compounds was carried out with a focus on the P4 moiety. Among the optimized compounds, 12b-f showed improved selectivity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tromboembolia
/
Serina Endopeptidases
/
Fator VIIa
/
Inibidores de Serina Proteinase
/
Química Farmacêutica
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Ano de publicação:
2008
Tipo de documento:
Article