title: Synthesis, stability and anticonvulsant activity of two new GABA prodrugs.
abstract: 4-(3,4-Dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl)-butyric acid (7) and its ester 6, two potential gamma-aminobutyric acid (GABA) prodrugs, were synthesized and studied to determine their stability in aqueous buffer and their susceptibility to undergo enzymatic hydrolysis in vitro (mouse plasma). Both compounds were fairly stable in aqueous media, (t1/2 = 68.2 h and 25.7 h, respectively). The 3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazine ring underwent enzymatic hydrolysis (t1/2 = 5.8 h) in compound 7, whereas in compound 6 it seemed not to be opened by mouse plasma esterases within the observation time (3h). Both compounds were tested for their anticonvulsant activity in pentetrazole (PTZ) treated mice, and showed significant activity. Compound 7, administered as sodium salt 8, was active at relatively low doses and can be considered a very interesting GABA prodrug.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Naples Federico II, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Palagiano
authors.forename: F P
authors.initials: FP
authors.lastname: Bonina
authors.forename: L
authors.initials: L
authors.lastname: Montenegro
authors.forename: A
authors.initials: A
authors.lastname: Biondi
authors.forename: L
authors.initials: L
authors.lastname: Sorrentino
authors.forename: A
authors.initials: A
authors.lastname: Capasso
authors.forename: P
authors.initials: P
authors.lastname: de Caprariis
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006868:Hydrolysis; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C106200:4-(3,4-dihydro-2,4-dioxo-2H-1,3--benzoxazin-3-yl)butyric acid ethyl ester; C106199:4-(3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl)butyric acid; D000927:Anticonvulsants; D048588:Benzoxazines; D010078:Oxazines; D011355:Prodrugs; D005680:gamma-Aminobutyric Acid