Carbonic Anhydrases have been recently validated as novel therapeutic targets in neuropathic pain. In this study, we combine the anticonvulsant propriety of spyrohydantoin and the CA inhibitor moiety of benzenesulfonamide to synthesize a novel series of spyrohydantoin bearing sulfonamides with strong activity against hCA II and VII. These isoforms are present in the nervous system and largely expressed both at the central as well as at peripheral level and can be modulated for pain relief. The crystal structures of hCA II in complex with selected compounds 5a-c demonstrate the importance of the tail in the binding modes within the isoform. Finally, in vivo, in an animal model of oxaliplatin induced neuropathy, compounds with organoselenium tails (8b-c) showed potent neuropathic pain attenuating effects. Taken together, these data strongly suggest the translational utility of these inhibitors as novel pain relievers. (C) 2019 Elsevier Masson SAS. All rights reserved.

Benzensulfonamides bearing spyrohydantoin moieties act as potent inhibitors of human carbonic anhydrases {II} and {VII} and show neuropathic pain attenuating effects / Andrea Angeli; Lorenzo Di Cesare Mannelli; Carla Ghelardini; Thomas S. Peat; Gianluca Bartolucci; Marta Menicatti; Fabrizio Carta; Claudiu T. Supuran. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1768-3254. - ELETTRONICO. - 177:(2019), pp. 188-197. [10.1016/j.ejmech.2019.05.058]

Benzensulfonamides bearing spyrohydantoin moieties act as potent inhibitors of human carbonic anhydrases {II} and {VII} and show neuropathic pain attenuating effects

Andrea Angeli;Lorenzo Di Cesare Mannelli;Carla Ghelardini;Gianluca Bartolucci;Marta Menicatti;Fabrizio Carta;Claudiu T. Supuran
2019

Abstract

Carbonic Anhydrases have been recently validated as novel therapeutic targets in neuropathic pain. In this study, we combine the anticonvulsant propriety of spyrohydantoin and the CA inhibitor moiety of benzenesulfonamide to synthesize a novel series of spyrohydantoin bearing sulfonamides with strong activity against hCA II and VII. These isoforms are present in the nervous system and largely expressed both at the central as well as at peripheral level and can be modulated for pain relief. The crystal structures of hCA II in complex with selected compounds 5a-c demonstrate the importance of the tail in the binding modes within the isoform. Finally, in vivo, in an animal model of oxaliplatin induced neuropathy, compounds with organoselenium tails (8b-c) showed potent neuropathic pain attenuating effects. Taken together, these data strongly suggest the translational utility of these inhibitors as novel pain relievers. (C) 2019 Elsevier Masson SAS. All rights reserved.
2019
177
188
197
Andrea Angeli; Lorenzo Di Cesare Mannelli; Carla Ghelardini; Thomas S. Peat; Gianluca Bartolucci; Marta Menicatti; Fabrizio Carta; Claudiu T. Supuran
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1321031
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