Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase

Daniela* Pizzirani; Anders* Bach; Natalia Realini; Andrea Armirotti; Luisa Mengatto; Inga Bauer; Stefania Girotto; Chiara Pagliuca; Marco De Vivo; Maria Summa; Alison Ribeiro; Daniele (*Shared 1st authors) (Inside front cover) Piomelli

doi:10.1002/anie.201409042

Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase

Daniela* Pizzirani, Anders* Bach, Natalia Realini, Andrea Armirotti, Luisa Mengatto, Inga Bauer, Stefania Girotto, Chiara Pagliuca, Marco De Vivo, Maria Summa, Alison Ribeiro, Daniele (*Shared 1st authors) (Inside front cover) Piomelli

22 Citations (Scopus)

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 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.

Original language	English
Journal	Angewandte Chemie (International ed. in English)
Volume	54
Pages (from-to)	485–489
Number of pages	5
ISSN	1433-7851
DOIs	https://doi.org/10.1002/anie.201409042
Publication status	Published - 7 Jan 2015

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Pizzirani, D., Bach, A., Realini, N., Armirotti, A., Mengatto, L., Bauer, I., Girotto, S., Pagliuca, C., De Vivo, M., Summa, M., Ribeiro, A., & Piomelli, D. S. . A. (2015). Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase. Angewandte Chemie (International ed. in English), 54, 485–489. https://doi.org/10.1002/anie.201409042

Pizzirani, D, Bach, A, Realini, N, Armirotti, A, Mengatto, L, Bauer, I, Girotto, S, Pagliuca, C, De Vivo, M, Summa, M, Ribeiro, A & Piomelli, DSA 2015, 'Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase', Angewandte Chemie (International ed. in English), vol. 54, pp. 485–489. https://doi.org/10.1002/anie.201409042

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title = "Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase",

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 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.",

author = "Daniela* Pizzirani and Anders* Bach and Natalia Realini and Andrea Armirotti and Luisa Mengatto and Inga Bauer and Stefania Girotto and Chiara Pagliuca and {De Vivo}, Marco and Maria Summa and Alison Ribeiro and Piomelli, {Daniele (*Shared 1st authors) (Inside front cover)}",

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AU - Pizzirani, Daniela

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AU - Mengatto, Luisa

AU - Bauer, Inga

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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.

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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.

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DO - 10.1002/anie.201409042

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JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

ER -

Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase

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