| Abstract
| - A series ofN-(phenylacetyl)trifluoromethanesulfonamides(3a−g) was prepared accordingtothe Topliss scheme in order to determine if aryl substitutents wouldinfluence anticonvulsantactivity. In initial (phase I) screening and quantitative (phaseII) evaluation, all sevencompounds exhibited significant activity against MES- and scMet-inducedseizures. N-(Phenylacetyl)trifluoromethanesulfonamide (3a) was thenadvanced through five additionaltesting phases (phases III−VII). Compound 3adisplayed good oral bioavailability, low toxicity,and a larger protective index in mice than the prototype drugs,phenytoin, phenobarbital,valproate, and ethosuximide. Additionally, 3a exhibiteda longer time to peak effect in alltests and a greater 24-h margin of safety(HD50/ED50) than the prototypes. Compound3ablocked picrotoxin-induced seizures but was ineffective againstseizures induced by bicucullineor strychnine. In vitro receptor binding studiesrevealed that 3a did not displace[3H]-labeledγ-aminobutyric acid or [3H]-labeled flunitrazepam, andtolerance did not develop during 5-daychronic administration.
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