RESUMO
Phosphonamidate 3a of methoxymethylphosphonic acid (MMPA) with propofol (1) and l-alanine ethyl ester was found to be an efficient scaffold for the oral delivery of compound 1. The synthesis and evaluation of MMPA based phosphonamidates of compound 1, HSK3486 (2), and other phenolic drugs revealed the general application of MMPA as the effective delivery vehicle for phenolic drugs. On the basis of plasma concentrations of compound 1 and SN38 (14), the oral bioavailability of compound 3a and 15 in beagle dogs was found to be 97.6% and 34.1%, respectively.
Assuntos
Portadores de Fármacos , Hipnóticos e Sedativos/administração & dosagem , Organofosfonatos/administração & dosagem , Propofol/administração & dosagem , Administração Oral , Animais , Cães , Feminino , Hipnóticos e Sedativos/farmacocinética , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Propofol/farmacocinética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
In the present study on the development of new anticonvulsants, twenty new 6-methyl-1-substituted-4,6-diazaspiro[2.4]heptane-5,7-diones were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens. Their neurotoxicity was determined by the rotorod test. In this series, all of the alkyl- and aryl-substituted 5,5-cyclopropanespirohydantoins showed more or less protection against MES and/or scPTZ models. The most active of the series was 6-methyl-1-(4-(methylsulfonyl)phenyl)-4,6-diazaspiro[2.4]heptane-5,7-dione (6 t), which showed a MES ED(50) value of 12.5 mg/kg in mice. The median toxic dose (TD(50)) was 310 mg/kg, providing compound 6 t with a protection index (PI = TD(50)/ED(50)) of 24.8 in the MES test which is better than phenytoin.