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

We report the regioselective chemical derivatization of (R)-2-((4-aminophenethyl)amino)-1-phenylethan-1-ol, the primary metabolite of the β3-Adrenergic Receptor (β3-AR) agonist mirabegron, with prototypical Carbonic Anhydrase Inhibitors (CAIs) to afford the carbamates 10-14 and the ureido derivatives 15-18. Such compounds were endowed in vitro with distinct inhibition profiles for the human (h) Carbonic Anhydrases (CAs) and showed preferential agonisms for the β3-AR subtype. Among them, 14 induced remarkable intraocular pressure (IOP) lowering in an in vivo transient model of ocular hypertension, with the maximal effect at 120 min post-administration at 1% w/v concentration. Furthermore, the high stability of the compounds in rabbit plasma and their ability to induce full vasodilation in isolated porcine retinal arteries suggested that the observed in vivo effects likely result from a combination of conventional aqueous humor reduction and modulation of ocular vascular tone, both of which are mediated by CAs and β-ARs. The pronounced melanosomal accumulation of representative compounds 14 and 16 highlights their potential as ideal candidates for evaluating pharmacokinetic profiles in ophthalmic applications. The results of this study provide strong evidence for the biomedical repurposing of a neglected metabolite through a novel class of dual-targeting ligands, also offering a promising strategy to help counteract the ongoing decline in drug discovery.