Sultam based Carbonic Anhydrase VII inhibitors for the management of neuropathic pain
Autor: | Katia D'Ambrosio, Fabrizio Carta, Simona Maria Monti, Andrea Angeli, Elena Lucarini, Giuseppina De Simone, Ozlem Akgul, Lorenzo Di Cesare Mannelli, Claudiu T. Supuran, Martina Buonanno, Carla Ghelardini |
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Rok vydání: | 2022 |
Předmět: |
Male
Models Molecular Drug Gene isoform Errors media_common.quotation_subject Thiazines Pharmacology Crystallography X-Ray Neuropathic pain Sulfonamide Mice Structure-Activity Relationship Crystal-Structures Models Carbonic anhydrase Drug Discovery medicine Animals Humans Potency Moiety Carbonic Anhydrase Inhibitors Carbonic Anhydrases media_common Induced Peripheral Neuropathy Sultam Carbonic anhydrase VII Dose-Response Relationship Drug Molecular Structure biology Chemistry Organic Chemistry Active site General Medicine Oxaliplatin Neuroprotective Agents Duloxetine biology.protein Neuralgia medicine.drug |
Zdroj: | European Journal of Medicinal Chemistry. 227:113956 |
ISSN: | 0223-5234 |
Popis: | We report a series of compounds 1-17 derived from the antiepileptic drug Sulthiame (SLT) from which both the benzenesulfonamide and the sultam moiety were retained. All compounds were tested in vitro for their inhibition activity against the human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, VII, IX and XII isoforms. Among the series, derivatives 1 and 11 showed great enhancement of both inhibition potency and selectivity towards the hCA VII isoform, when compared to the reference SLT drug. The binding mode of 11 within the hCA VII active site was deciphered by means of X-ray crystallography and revealed the sultam moiety being exposed to the rim of the active site. In vivo experiments on a model of neuropathic pain induced by oxaliplatin clearly showed 11 being an effective pain relieving agent and therefore worth of further exploitation towards the validation of the hCA VII as new target for the management of neuropathies. (C) 2021 Elsevier Masson SAS. All rights reserved. Scientific and Technical Research Council of Turkey [TUBITAK117S516]; Ege University [16-ECZ-012]; Bando di Ateneo per il Finanziamento di Progetti Competitivi per Ricercatori a Tempo Determinato (RTD) dell'Universita di Firenze - 2020-2021; Fondazione Cassa di Risparmio di Firenze [ECR2018.1001] Ozlem Akgul (O.A.) is grateful to The Scientific and Technical Research Council of Turkey [TUBITAK117S516] and Ege University [16-ECZ-012].; Fabrizio Carta (F.C.) is grateful to Bando di Ateneo per il Finanziamento di Progetti Competitivi per Ricercatori a Tempo Determinato (RTD) dell'Universita di Firenze -2020-2021 and Fondazione Cassa di Risparmio di Firenze (Grant Number ECR2018.1001) which partially funded this work. |
Databáze: | OpenAIRE |
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