Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action

The “tail
approach” has become a milestone in human
carbonic anhydrase inhibitor (hCAI) design for various therapeutics,
including antiglaucoma agents. Besides the classical hydrophobic/hydrophilic
division of hCAs active site, several subpockets have been identified
at the middle/outer active sites rim, which could be targeted to increase
the CAI isoform selectivity. This postulate is explored here by three-tailed
benzenesulfonamide CAIs (TTI) to fully exploit such amino
acid differences among hCAs. In this proof-of-concept study, an extensive
structure–activity relationship (SAR) study was carried out
with 32 such benzenesulfonamides differing in tails combination that
were assayed for hCAs I, II, IV, and XII inhibition. A structural
study was undertaken by X-ray crystallography and in silico tools to assess the ligand/target interaction mode. The most active
and selective inhibitors against isoforms implicated in glaucoma were
assessed in a rabbit model of the disease achieving an intraocular
pressure-lowering action comparable to the clinically used dorzolamide.