Soft Drugs. 7. Soft β-Blockers for Systemic and Ophthalmic Use

Article abstract of DOI:10.1021/jm00403a028

The "inactive metabolite approach" used to design a series of "soft" drugs derived from the acidic metabolite of metoprolol.Pharmacokinetic and pharmacodynamic properties of these novel "soft" β-adrenoceptor antagonists were determined: half-lives in human blood ranged from 5 to 754 min.The rates of in vivo disappearance of representative slow, medium, and fast hydrolyzing esters were determined in rats.In each case rapid and quantitative conversion to the corresponding free acid was observed.This suggests a facile, one-step degradation to the predicted major metabolite.The compounds were tested for their ability to decrease intraocular pressure in a rabbit model.Five of the new compounds exerted an ocular hypotensive action comparable to or greater than of the reference compound, timolol maleate, and with a prolonged duration of action in some cases.In contrast the new compounds showed reduced and shorter duration systemic activity.The adamantylethyl ester emerges as a potentially effective antiglaucoma agent with significantly improved site-specific activity.