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Soft drugs. 7. Soft beta-blockers for systemic and ophthalmic use
N Bodor1, A A el-Koussi, M Kano
1University of Florida, College of Pharmacy, Center for Drug Design and Delivery, J. Hillis Miller Health Center, Gainesville 32610.
Journal of Medicinal Chemistry
|August 1, 1988
Summary
New "soft" beta-blockers, designed using an inactive metabolite approach, show promising ocular hypotensive effects with reduced systemic activity. The adamantylethyl ester is a potential glaucoma treatment with improved site-specific action.
Area of Science:
- Pharmacology
- Medicinal Chemistry
Background:
- The inactive metabolite approach is a strategy for designing 'soft' drugs.
- Metoprolol's acidic metabolite served as a basis for developing novel beta-adrenoceptor antagonists.
Purpose of the Study:
- To design and characterize novel 'soft' beta-adrenoceptor antagonists.
- To evaluate their pharmacokinetic, pharmacodynamic, and ocular hypotensive properties.
Main Methods:
- Synthesis of 'soft' beta-blockers based on metoprolol's metabolite.
- Determination of pharmacokinetic parameters (half-life) in human blood.
- In vivo hydrolysis studies in rats.
- Ocular hypotensive activity assessment in a rabbit model.
Main Results:
- Compounds exhibited half-lives in human blood from 5 to 754 minutes.
- In vivo studies showed rapid conversion to the free acid metabolite.
- Five compounds demonstrated ocular hypotensive effects comparable to or exceeding timolol maleate.
- Reduced and shorter duration of systemic activity was observed compared to ocular effects.
Conclusions:
- The designed 'soft' beta-blockers offer prolonged ocular hypotensive action with reduced systemic exposure.
- The adamantylethyl ester shows potential as an effective antiglaucoma agent with enhanced site-specific activity.