Repurposing Drug Metabolites into Dual β-Adrenergic Receptor-Carbonic Anhydrase Modulators as Potential Tools for...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Ophthalmology

Background:

• Mirabegron is a beta-3 Adrenergic Receptor (β3-AR) agonist used for overactive bladder.
• Its primary metabolite, (R)-2-((4-aminophenethyl)amino)-1-phenylethan-1-ol, has been largely unexplored.
• Carbonic Anhydrase Inhibitors (CAIs) are used to treat glaucoma by reducing intraocular pressure (IOP).

Purpose of the Study:

• To synthesize and characterize novel dual-targeting compounds combining CAI and β3-AR agonist properties.
• To evaluate the in vitro and in vivo efficacy of these compounds, particularly for lowering IOP.
• To explore the potential of these derivatives for ophthalmic applications and drug discovery.

Main Methods:

• Regioselective chemical derivatization of mirabegron's primary metabolite.
• In vitro inhibition assays against human Carbonic Anhydrases (hCAs).
• In vitro assessment of β3-AR subtype agonism.
• In vivo evaluation of intraocular pressure (IOP) reduction in a transient ocular hypertension model.
• In vitro stability studies in rabbit plasma and vasodilation assays in isolated porcine retinal arteries.
• Melanosomal accumulation studies of key compounds.

Main Results:

• Synthesis of novel carbamate (10-14) and ureido (15-18) derivatives.
• Compounds exhibited distinct hCA inhibition profiles and preferential β3-AR agonism.
• Compound 14 demonstrated significant IOP lowering in vivo, with maximal effect at 120 min.
• Compounds showed high plasma stability and induced vasodilation in retinal arteries.
• Representative compounds (14, 16) showed pronounced melanosomal accumulation.

Conclusions:

• The novel dual-targeting ligands, derived from a mirabegron metabolite, show promise for treating ocular conditions.
• The compounds' mechanism likely involves both aqueous humor reduction and ocular vascular tone modulation.
• This study highlights the potential for biomedical repurposing and offers a new strategy for drug discovery.