title: Synthesis, hydrolysis, and intraocular pressure lowering effects of fadolmidine prodrugs.
abstract: The objective of this study was to synthesize and evaluate various esters of fadolmidine, a novel alpha2-adrenergic agonist, as potential ophthalmic prodrugs. All studied prodrugs released the parent drug (i.e., fadolmidine) quantitatively via enzymatic hydrolysis in 80% human serum. The pivalyl ester was considered to be the most promising prodrug in this series, due to its good chemical stability (pH 5.0; 37 degrees C; t(1/2)=310 days) and optimal lipophilicity (logP(app)=1.8; 1-octanol/phosphate buffer, pH 5.0), and was selected for further evaluation of its intraocular pressure (IOP) lowering effects in normotensive rabbits. The pivalyl ester showed increased IOP lowering ability when compared to an equimolar dose of fadolmidine, which was probably due to its increased lipophilicity and subsequent enhanced corneal penetration. The duration of action for the pivalyl ester was also longer than that of fadolmidine.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Riku
authors.initials: R
authors.lastname: Niemi
authors.forename: Juhani
authors.initials: J
authors.lastname: Huuskonen
authors.forename: Krista
authors.initials: K
authors.lastname: Laine
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
mesh_terms: D000818:Animals; D006868:Hydrolysis; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D012995:Solubility
chemical_list: D007093:Imidazoles; D007189:Indans; D011355:Prodrugs; C400294:radolmidine