Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation.
Bioorg Med Chem Lett
; 97: 129541, 2024 01 01.
Article
em En
| MEDLINE
| ID: mdl-37952596
ABSTRACT
Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Metaloproteinase 9 da Matriz
/
Precursores Enzimáticos
Idioma:
En
Revista:
Bioorg Med Chem Lett
/
Bioorg. med. chem. lett
/
Bioorganic & medicinal chemistry letters
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Japão
País de publicação:
Reino Unido