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

Journal of Medicinal Chemistry
Alessio NocentiniClaudiu T Supuran

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.

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Citations

Jun 21, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Alessio NocentiniClaudiu T Supuran
Aug 23, 2019·Expert Opinion on Drug Discovery·Alessio Nocentini, Claudiu T Supuran
Apr 17, 2020·Journal of Enzyme Inhibition and Medicinal Chemistry·Aleksandrs PustenkoClaudiu T Supuran
Sep 6, 2019·Expert Opinion on Therapeutic Patents·Alessio Nocentini, Claudiu T Supuran
Oct 1, 2019·Expert Opinion on Therapeutic Patents·Claudiu T Supuran
Oct 10, 2019·Expert Opinion on Therapeutic Patents·Claudiu T SupuranFabrizio Carta
Aug 7, 2019·Expert Opinion on Therapeutic Patents·Paolo GuglielmiGiovanna Poce
Apr 5, 2020·Biomolecules·Jacob AndringRobert McKenna
Sep 13, 2019·Expert Opinion on Therapeutic Patents·Silvia Bua, Claudiu T Supuran
Aug 12, 2019·European Journal of Medicinal Chemistry·Damiano TaniniClaudiu T Supuran
Oct 12, 2019·Bioorganic Chemistry·Alessio NocentiniClaudiu T Supuran
Apr 30, 2021·Expert Opinion on Drug Discovery·Francesco MincioneClaudiu T Supuran
May 21, 2021·Clinical Science·Claudiu T Supuran
Jul 31, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Claudiu T Supuran
Jun 3, 2020·Journal of Medicinal Chemistry·Kuei-Ju ChengJing-Ping Liou

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