L-653,328: an ocular hypotensive agent with modest beta receptor blocking activity.

Area of Science:

• Ophthalmology
• Pharmacology
• Drug Delivery

Background:

• Elevated intraocular pressure (IOP) is a risk factor for glaucoma.
• Developing effective IOP-lowering agents with minimal side effects is crucial.
• Prodrug strategies can enhance ocular drug penetration and efficacy.

Purpose of the Study:

• To evaluate the efficacy of L-653,328, an acetate ester prodrug, in reducing intraocular pressure (IOP) in rabbits.
• To compare the ocular penetration and IOP-lowering effects of L-653,328 with its active moiety, L-652,698, and established beta-blockers.
• To assess the extraocular beta-adrenoceptor blockade of L-653,328 and its active moiety.

Main Methods:

• L-653,328 and L-652,698 solutions were instilled into the eyes of alpha-chymotrypsinized rabbits to measure IOP reduction.
• The efficacy of L-653,328 and L-652,698 was compared to timolol and betaxolol at equivalent doses.
• Extraocular beta-adrenoceptor blockade was assessed by measuring heart rate and blood pressure changes in response to isoproterenol administration in conscious rabbits.

Main Results:

• L-653,328 significantly decreased elevated IOP in a dose-dependent manner.
• L-652,698 demonstrated activity at higher concentrations, while L-653,328 showed efficacy at lower doses, indicating enhanced penetration.
• L-653,328 exhibited significantly less extraocular beta-adrenoceptor blockade compared to timolol and betaxolol, attributed to the modest affinity of L-652,698 for beta-adrenoceptors.

Conclusions:

• L-653,328 serves as an effective prodrug for enhancing ocular penetration of L-652,698.
• L-653,328 demonstrates potent IOP-lowering effects with a reduced propensity for systemic side effects due to limited extraocular beta-adrenoceptor blockade.
• These findings suggest L-653,328 as a promising agent for managing elevated IOP.