Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives.
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.
['Odi|Reem|R|', 'Bibi|David|D|', 'Shusterman|Bella|B|', 'Erenburg|Natalia|N|', 'Shaul|Chanan|C|', 'Supuran|Claudiu T|CT|0000-0003-4262-0323', 'Nocentini|Alessio|A|0000-0003-3342-702X', 'Bialer|Meir|M|']
D000818:Animals D000927:Anticonvulsants D019540:Area Under Curve D001921:Brain D002219:Carbamates D002256:Carbonic Anhydrases D002490:Central Nervous System D004597:Electroshock D008297:Male D020033:Protein Isoforms D051381:Rats D017207:Rats, Sprague-Dawley D012640:Seizures D012997:Solvents D013237:Stereoisomerism
pharmacokinetics CNS-active carbamate antiepileptic activity carbonic anhydrase inhibition