1. Academic Validation
  2. Repurposing Drug Metabolites into Dual β-Adrenergic Receptor-Carbonic Anhydrase Modulators as Potential Tools for Ocular Disorders

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

  • J Med Chem. 2025 Sep 11;68(17):18579-18596. doi: 10.1021/acs.jmedchem.5c01459.
Andrea Ammara 1 Alessandra Carone 1 Laura Lucarini 2 Silvia Sgambellone 2 Silvia Marri 2 Serafina Villano 2 Rosanna Matucci 2 Gerta Luga 2 Chiara Fittipaldi 2 Riccardo Pecori 3 Giuseppe Pieraccini 4 Claudia Di Serio 5 Andrea García-Llorca 6 Thor Eysteinsson 6 Stanislav Kalinin 7 Julius Aleksi Olavi Viita 7 Arto Urtti 7 Fabrizio Carta 1 Silvia Selleri 1 Claudiu T Supuran 1
Affiliations

Affiliations

  • 1 NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, Florence 50019, Italy.
  • 2 Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale Gaetano Pieraccini, 6, Florence 50139, Italy.
  • 3 German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • 4 Department of Health Sciences, CISM Mass Spectrometry Centre, University of Florence, Viale Gaetano Pieraccini 6, Florence 50139, Italy.
  • 5 Experimental and Clinical Medicine Department, Geriatric Intensive Care Unit, University of Florence, Azienda Ospedaliera Universitaria Careggi, Viale Gaetano Pieraccini 6, Florence 50139, Italy.
  • 6 Department of Physiology, Biomedical Center, Faculty of Medicine, University of Iceland, Reykjavík 101, Iceland.
  • 7 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonrinne 3, Kuopio 70211, Finland.
Abstract

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.

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