Alprenoxime Hydrochloride

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 t90 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 approximately 7.0, the t90 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.

A new site-specific chemical delivery system (CDS) for alprenolol was designed and investigated as a potential novel antiglaucoma agent. The effect of this compound, alprenoxime (AO), on the intraocular pressure (IOP) of rabbits was evaluated after its uni- and bilateral administration. AO produced significant reduction of the IOP starting at 30 min and lasting for more than 6 hr after its topical administration. Both in rats and in rabbits the i.v. bolus injection of AO (6 mg/kg) led to insignificant transient bradycardia, while no activity was found after oral or topical administration. Alprenolol (ALP) in a similar dose produced a sustained and significant bradycardia for more than 30 min. When the beta-adrenergic blocking activity was assessed against isoprenaline-tachycardia, the same results were obtained, i.e., AO led to a transient brief activity, whereas ALP produced a significant long-lasting beta blockade. These results support the potent ocular hypotensive action and the weak systemic beta-adrenergic blocking and cardiovascular activity of AO: a significant improvement in the therapeutic index. This finding recommends alprenoxime as a potent site-specific antiglaucoma agent with minimal systemic side effects.