Benzoxazolone carboxamides: potent and systemically active inhibitors of intracellular acid ceramidase.
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 in 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.
Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy).
Daniela
D
Pizzirani
Anders
A
Bach
Natalia
N
Realini
Andrea
A
Armirotti
Luisa
L
Mengatto
Inga
I
Bauer
Stefania
S
Girotto
Chiara
C
Pagliuca
Marco
M
De Vivo
Maria
M
Summa
Alison
A
Ribeiro
Daniele
D
Piomelli
D000577:Amides / Q000737:chemistry*; D001583:Benzoxazoles / Q000737:chemistry*; D055572:Ceramidases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*
D000577:Amides; D001583:Benzoxazoles; D004791:Enzyme Inhibitors; C017057:benzoxazolone; D055572:Ceramidases
acid ceramidase; cancer; ceramide; enzyme inhibition; sphingosine-1-phosphate