Stereoselective pharmacokinetic and pharmacodynamic analysis of a CNS-active sulphamoylphenyl carbamate derivative

David Bibi, Bella Shusterman, Alessio Nocentini, Claudiu T. Supuran, Meir Bialer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

3-Methylpentyl(4-sulphamoylphenyl)carbamate (MSPC) came as the most potent compound out of a new series of carbamates composed of phenyl-ethanol or branched aliphatic alcohols, and 4-benzenesulphonamide-carbamic acid. In this study, the anticonvulsant activity and pharmacokinetics (PKs) of MSPC-two individual enantiomers were comparatively analysed in rats as well as their carbonic anhydrase (CA) inhibition. The anticonvulsant activity of MSPC enantiomers was evaluated at the rat-maximal electroshock (MES) test, and their CA inhibition evaluated. (R)-MSPC had a 29% higher clearance and consequently, a lower plasma exposure area under the curve (AUC) than (S)-MSPC and racemic-MSPC. Nevertheless, (R)-MSPC had a better brain permeability than its (S)-enantiomer with brain-to-plasma-(AUC)-ratio (BPR) of 2.07 ((R)-enantiomer), 1.85 (racemate), and 0.79 ((S)-enantiomer). As a whole body (in vivo) pharmacodynamic (PD) measure, MSPC-anticonvulsant maximal electroshock seizure (MES) activity was less enantioselective than MSPC-CA inhibition. The lack of significant differences between racemic-MSPC and its individual enantiomers suggest that their anticonvulsant activity might be due to multiple mechanisms of action.

Original languageEnglish
Pages (from-to)1078-1082
Number of pages5
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume34
Issue number1
DOIs
StatePublished - 1 Jan 2019

Bibliographical note

Publisher Copyright:
© 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • 4-aminobenzenesulphonamides
  • carbonic anhydrase inhibition
  • CNS-active carbamates
  • New antiepileptic drugs
  • pharmacokinetics

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