Improved Delivery through Biological Membranes. 26. Design, Synthesis, and Pharmacological Activity of a Novel Chemical Delivery System for β-Adrenegic Blocking Agents

Article abstract of DOI:10.1021/jm00396a015

Novel ketoxime analogues of known β-blockers (propranolol, timolol, carteolol) and tested as potential site-specific chemical delivery systems.It was assumed that a hydrolysis-reduction sequence could produce the active β-blockers in the iris-ciliary body.It was found that some of these bioprecursors are remarcable active in reducing intraocular pressure in rabbits.The ketoxime derivative of propranolol is more effective and much less irritant than its parent β-blocker.While the ketoximes also displayed activity on isoprenaline-induced tachycardia after iv administration, they were void of activity when given orally.Propranolol was found for a prolonged time and in significant concentrations in the rabbit's eye following topical administration of its ketoxime precursor; however, the inactive ketoximes apparently were not converted to the corresponding β-blockers in the eye.A correlation was found between the physicochemical properties of the ketoximes and their conversion to the amino alcohol and thus their subsequent activity.The results suggest that at least some of the ketoxime precursors could have a use as antiglaucoma agents without systemic side effects.