SEQUENTIAL BIOACTIVATION OF METHOXIME ANALOGS OF BETA-ADRENERGIC ANTAGONISTS IN THE EYE

Selected beta-adrenoreceptor antagonists are the antiglaucoma drugs of first choice in most cases. However, a number of significant central nervous system (CNS), cardiovascular and respiratory side-effects following topical ocular installation of beta-blockers have also been reported. Site- and stereo-specific delivery to the eye of beta-blockers was achieved by application of a sequential bioactivation of the chemical delivery system (CDS) analogs of these drugs, which are converted to the active beta-blockers only in the eye, thus systemic side effects are avoided. The corresponding ketoxime analogs of the various beta-blockers were successfully applied and one of them, Alprenoxime, was tested in humans. The main problem with these compounds, however, is formulation stability: Alprenoxime has a t(90) of only 2-3 months. Thus, alternate structures were searched. Methoxime analogs of selected beta-blockers were synthesized and their chemical stability established at different pH's. Subsequently, their in vivo sequential enzymatic conversion was confirmed using HPLC. Comparative intraocular pressure (IOP) reducing activity of the methoximes were then studied using normotensive rabbits. The methoxime analogs showed significantly improved hydrolytic stability at pH similar to 7.0, the t(90) is over 1 year. The in vivo sequential bioactivation, however, proceeds similarly to the oximes. The intermediate ketones and the active beta-blockers can be detected in the various eye compartments at different time intervals following topical administration of the methoximes. The mechanism of the eye-selective bioactivation and the results of the IOP reducing activity studies will be discussed.