Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase
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Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase. / Pizzirani, Daniela*; Bach, Anders*; Realini, Natalia; Armirotti, Andrea; Mengatto, Luisa; Bauer, Inga; Girotto, Stefania; Pagliuca, Chiara; De Vivo, Marco; Summa, Maria; Ribeiro, Alison; Piomelli, Daniele (*Shared 1st authors) (Inside front cover).
In: Angewandte Chemie (International ed. in English), Vol. 54, 2015, p. 485–489.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase
AU - Pizzirani, Daniela
AU - Bach, Anders
AU - Realini, Natalia
AU - Armirotti, Andrea
AU - Mengatto, Luisa
AU - Bauer, Inga
AU - Girotto, Stefania
AU - Pagliuca, Chiara
AU - De Vivo, Marco
AU - Summa, Maria
AU - Ribeiro, Alison
AU - Piomelli, Daniele (Shared 1st authors) (Inside front cover)
N1 - © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1002/anie.201409042
DO - 10.1002/anie.201409042
M3 - Journal article
C2 - 25395373
VL - 54
SP - 485
EP - 489
JO - Angewandte Chemie International Edition
JF - Angewandte Chemie International Edition
SN - 1433-7851
ER -
ID: 127818885