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

We report the regioselective chemical derivatization of (<i>R</i>)-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 <b>10-14</b> and the ureido derivatives <b>15-18</b>. Such compounds were endowed <i>in vitro</i> with distinct inhibition profiles for the human (h) Carbonic Anhydrases (CAs) and showed preferential agonisms for the β₃-AR subtype. Among them, <b>14</b> induced remarkable intraocular pressure (IOP) lowering in an <i>in vivo</i> 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 <i>in vivo</i> 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 <b>14</b> and <b>16</b> 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.