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@ARTICLE{Ammara:304121,
      author       = {A. Ammara and A. Carone and L. Lucarini and S. Sgambellone
                      and S. Marri and S. Villano and R. Matucci and G. Luga and
                      C. Fittipaldi and R. Pecori$^*$ and G. Pieraccini and C. Di
                      Serio and A. García-Llorca and T. Eysteinsson and S.
                      Kalinin and J. A. O. Viita and A. Urtti and F. Carta and S.
                      Selleri and C. T. Supuran},
      title        = {{R}epurposing {D}rug {M}etabolites into {D}ual
                      β-{A}drenergic {R}eceptor-{C}arbonic {A}nhydrase
                      {M}odulators as {P}otential {T}ools for {O}cular
                      {D}isorders.},
      journal      = {Journal of medicinal chemistry},
      volume       = {nn},
      issn         = {0095-9065},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {DKFZ-2025-01784},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      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.},
      cin          = {D150},
      ddc          = {610},
      cid          = {I:(DE-He78)D150-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40857102},
      doi          = {10.1021/acs.jmedchem.5c01459},
      url          = {https://inrepo02.dkfz.de/record/304121},
}