Synthesis and structure-activity relationships of 4-alkynyloxy phenyl sulfanyl, sulfinyl, and sulfonyl alkyl hydroxamates as tumor necrosis factor-alpha converting enzyme and matrix metalloproteinase inhibitors.
J Med Chem
; 47(25): 6255-69, 2004 Dec 02.
Article
en En
| MEDLINE
| ID: mdl-15566296
ABSTRACT
A series of 4-alkynyloxy phenyl sulfanyl, sulfinyl and sulfony alkyl and piperidine-4-carboxylic acid hydroxamides were synthesized. Their structure-activity relationships, against tumor necrosis factor-alpha (TACE) and matrix metalloproteinase (MMP) inhibitor activities, are presented by investigating the oxidation state on sulfur and altering the P1' substituent. The sulfonyl derivatives 20-24 carrying a 4-butynyloxy moiety were selective TACE inhibitors over the MMPs tested. The sulfinyl derivatives showed a preference for a specific oxidation on sulfur as in compounds 25-28. The selectivity over MMPs was also demonstrated in the sulfonyl series. The enhanced cellular activity was achieved upon incorporating a butynyloxy substituent in the piperidene series. Compounds 64 and 65 were potent inhibitors of TNF-alpha release in the mouse at 100 mg/kg po.
Buscar en Google
Bases de datos:
MEDLINE
Asunto principal:
Sulfuros
/
Sulfonas
/
Sulfóxidos
/
Metaloendopeptidasas
/
Inhibidores de la Metaloproteinasa de la Matriz
/
Ácidos Hidroxámicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2004
Tipo del documento:
Article
País de afiliación:
Estados Unidos