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

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.