title: Cycloserine fatty acid derivatives as prodrugs: synthesis, degradation and in vitro skin permeability.
abstract: Various 4,5-dihydroisoxazol-3-yl fatty acid ester derivatives of cycloserine were synthesized to improve skin permeation of cycloserine. The ester derivatives were prepared by using the tert-butoxycarbonyl (t-Boc) protection strategy. The 4,5-dihydroisoxazol-3-yl esters were readily hydrolysed in an aqueous buffer solution, and the degradation profiles showed both specific acid and specific base catalysis. In 50% human serum the formation of cycloserine was observed, but enzymatic catalysis was limited. Delivery through hairless mouse skin was investigated, and the apparent permeability coefficient was measured based on the flux of cycloserine into the receptor phase. The skin permeation of cycloserine across the hairless mouse skin was increased up to 20-fold by the fatty acid esters. The 4,5-dihydroisoxazol-3-yl fatty acid esters of cycloserine can therefore be considered as new topical prodrugs with the potential use in treatment of various skin infections.
authors.affiliation: Faculty of Pharmacy, University of Iceland, Reykjavik.
authors.forename: Thorsteinn
authors.initials: T
authors.lastname: Thorsteinsson
authors.forename: Már
authors.initials: M
authors.lastname: Másson
authors.forename: Tomi
authors.initials: T
authors.lastname: Jarvinen
authors.forename: Tapio
authors.initials: T
authors.lastname: Nevalainen
authors.forename: Thorsteinn
authors.initials: T
authors.lastname: Loftsson
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D003523:Cycloserine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D005227:Fatty Acids / Q000737:chemistry*; D005260:Female; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008812:Mice, Hairless; D010539:Permeability; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism*
chemical_list: D000904:Antibiotics, Antitubercular; D005227:Fatty Acids; D011355:Prodrugs; D003523:Cycloserine