1. Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives
- Author
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Bella Shusterman, Claudiu T. Supuran, Natalia Erenburg, Reem Odi, David Bibi, Chanan Shaul, Meir Bialer, and Alessio Nocentini
- Subjects
Central Nervous System ,Male ,0301 basic medicine ,CNS-active ,medicine.medical_treatment ,Medicinal chemistry ,Rats, Sprague-Dawley ,lcsh:Chemistry ,0302 clinical medicine ,Protein Isoforms ,lcsh:QH301-705.5 ,Spectroscopy ,ED50 ,Carbonic Anhydrases ,Electroshock ,biology ,Pharmacokinetic pharmacodynamic ,Chemistry ,Brain ,carbamate ,Stereoisomerism ,General Medicine ,Computer Science Applications ,Area Under Curve ,Anticonvulsants ,pharmacokinetics ,Carbamate ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Pharmacokinetics ,antiepileptic activity ,Seizures ,Carbonic anhydrase ,medicine ,Animals ,Physical and Theoretical Chemistry ,Molecular Biology ,Organic Chemistry ,Enantioselective synthesis ,Rats ,030104 developmental biology ,Anticonvulsant ,lcsh:Biology (General) ,lcsh:QD1-999 ,Solvents ,biology.protein ,carbonic anhydrase inhibition ,Carbamates ,Enantiomer ,030217 neurology & neurosurgery - Abstract
We recently reported a new class of carbamate derivatives as anticonvulsants. Among these, 3-methylpentyl(4-sulfamoylphenyl)carbamate (MSPC) stood out as the most potent compound with ED50 values of 13 mg/kg (i.p.) and 28 mg/kg (p.o.) in the rat maximal electroshock test (MES). 3-Methylpropyl(4-sulfamoylphenyl)carbamate (MBPC), reported and characterized here, is an MSPC analogous compound with two less aliphatic carbon atoms in its structure. As both MSPC and MBPC are chiral compounds, here, we studied the carbonic anhydrase inhibitory and anticonvulsant action of both MBPC enantiomers in comparison to those of MSPC as well as their pharmacokinetic properties. Racemic-MBPC and its enantiomers showed anticonvulsant activity in the rat maximal electroshock (MES) test with ED50 values in the range of 19–39 mg/kg. (R)-MBPC had a 65% higher clearance than its enantiomer and, consequently, a lower plasma exposure (AUC) than (S)-MSBC and racemic-MSBC. Nevertheless, (S)-MBPC had a slightly better brain permeability than (R)-MBPC with a brain-to-plasma (AUC) ratio of 1.32 (S-enantiomer), 1.49 (racemate), and 1.27 (R-enantiomer). This may contribute to its better anticonvulsant-ED50 value. The clearance of MBPC enantiomers was more enantioselective than the brain permeability and MES-ED50 values, suggesting that their anticonvulsant activity might be due to multiple mechanisms of action.
- Published
- 2021
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