title: Synthesis, anticonvulsant properties and pharmacokinetic profile of novel 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide derivatives.
abstract: A series of novel derivatives of oxcarbazepine (5), 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide was synthesised and evaluated for their anticonvulsant activity and sodium channel blocking properties. The oxime 8 was found to be the most active compound from this series, displaying greater potency than its geometric isomer 9 and exhibiting also the highest protective index value. Importantly, the metabolic profile of 8 differs from the already established dibenz/b,f/azepine-5-carboxamide drugs such as 1 and 5 which undergo rapid and complete conversion in vivo to several biologically active metabolites. In contrast 8 is metabolised to only a very minor extent leading to the conclusion that the observed anti-convulsant effect is solely attributable to 8. It is concluded that 8 may be as effective as 1 and 5 at controlling seizures and that the low toxicity and consequently high protective index should provide the compound with an improved side-effect profile.
authors.affiliation: Department of Research & Development, Laboratory of Chemistry, BIAL, 4785 S., Mamede do Coronado, Portugal.
authors.forename: D A
authors.initials: DA
authors.lastname: Learmonth
authors.forename: J
authors.initials: J
authors.lastname: Benes
authors.forename: A
authors.initials: A
authors.lastname: Parada
authors.forename: D
authors.initials: D
authors.lastname: Hainzl
authors.forename: A
authors.initials: A
authors.lastname: Beliaev
authors.forename: M J
authors.initials: MJ
authors.lastname: Bonifácio
authors.forename: P M
authors.initials: PM
authors.lastname: Matias
authors.forename: M A
authors.initials: MA
authors.lastname: Carrondo
authors.forename: J
authors.initials: J
authors.lastname: Garrett
authors.forename: P
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D013045:Species Specificity
chemical_list: D000577:Amides; D000927:Anticonvulsants; D001381:Azepines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D002220:Carbamazepine