Benzoxazolone carboxamides: potent and systemically active inhibitors of intracellular acid ceramidase.
Angew Chem Int Ed Engl
; 54(2): 485-9, 2015 Jan 07.
Article
em En
| MEDLINE
| ID: mdl-25395373
ABSTRACT
The ceramides are a family of bioactive lipid-derived messengers involved in the control of cellular senescence, inflammation, and apoptosis. Ceramide hydrolysis by acid ceramidase (AC) stops the biological activity of these substances and influences survival and function of normal and neoplastic cells. Because of its central role in the ceramide metabolism, AC may offer a novel molecular target in disorders with dysfunctional ceramide-mediated signaling. Here, a class of benzoxazolone carboxamides is identified as the first potent and systemically active inhibitors of AC. Prototype members of this class inhibit AC with low nanomolar potency by covalent binding to the catalytic cysteine. Their metabolic stability and high inâ
vivo efficacy suggest that these compounds may be used as probes to investigate the roles of ceramide in health and disease, and that this scaffold may represent a promising starting point for the development of novel therapeutic agents.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzoxazóis
/
Inibidores Enzimáticos
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Ceramidases
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Amidas
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2015
Tipo de documento:
Article