The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations is one of the most clinically used treatment for glaucoma. A novel approach consisting of single-molecule, multitargeted compounds for the treatment of glaucoma is proposed here by designing compounds which concomitantly interact with the β-adrenergic and CA targets. Most derivatives of the two series of benzenesulfonamides incorporating 2-hydroxypropylamine moieties reported here exhibited striking efficacy against the target hCA II and XII, whereas a subset of compounds also showed significant modulation of β1- and β2-ARs. X-ray crystallography studies provided rationale for the observed hCA inhibition. The best dual-agents decreased IOP more effectively than clinically used dorzolamide, timolol, and the combination of them in an animal model of glaucoma. The reported evidence supports the proof-of-concept of β-ARs blocker-CAI hybrids for antiglaucoma therapy with an innovative mechanism of action.

Discovery of β-Adrenergic Receptors Blocker-Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma Therapy / Nocentini, Alessio; Ceruso, Mariangela; Bua, Silvia; Lomelino, Carrie L.; Andring, Jacob T.; McKenna, Robert; Lanzi, Cecilia; Sgambellone, Silvia; Pecori, Riccardo; Matucci, Rosanna; Filippi, Luca; Gratteri, Paola; Carta, Fabrizio; Masini, Emanuela; Selleri, Silvia*; Supuran, Claudiu T.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 61:(2018), pp. 5380-5394. [10.1021/acs.jmedchem.8b00625]

Discovery of β-Adrenergic Receptors Blocker-Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma Therapy

Nocentini, Alessio;Ceruso, Mariangela;Bua, Silvia;Lanzi, Cecilia;Sgambellone, Silvia;Pecori, Riccardo;Matucci, Rosanna;Filippi, Luca;Gratteri, Paola;Carta, Fabrizio;Masini, Emanuela;Selleri, Silvia;Supuran, Claudiu T.
2018

Abstract

The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations is one of the most clinically used treatment for glaucoma. A novel approach consisting of single-molecule, multitargeted compounds for the treatment of glaucoma is proposed here by designing compounds which concomitantly interact with the β-adrenergic and CA targets. Most derivatives of the two series of benzenesulfonamides incorporating 2-hydroxypropylamine moieties reported here exhibited striking efficacy against the target hCA II and XII, whereas a subset of compounds also showed significant modulation of β1- and β2-ARs. X-ray crystallography studies provided rationale for the observed hCA inhibition. The best dual-agents decreased IOP more effectively than clinically used dorzolamide, timolol, and the combination of them in an animal model of glaucoma. The reported evidence supports the proof-of-concept of β-ARs blocker-CAI hybrids for antiglaucoma therapy with an innovative mechanism of action.
2018
61
5380
5394
Nocentini, Alessio; Ceruso, Mariangela; Bua, Silvia; Lomelino, Carrie L.; Andring, Jacob T.; McKenna, Robert; Lanzi, Cecilia; Sgambellone, Silvia; Pecori, Riccardo; Matucci, Rosanna; Filippi, Luca; Gratteri, Paola; Carta, Fabrizio; Masini, Emanuela; Selleri, Silvia*; Supuran, Claudiu T.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1154170
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