Discovery of Potent Dual-Tailed Benzenesulfonamide Inhibitors of Human Carbonic Anhydrases Implicated in Glaucoma and in Vivo Profiling of Their Intraocular Pressure-Lowering Action

The design of three dual-tailed sulfonamide
series 11a–11g, 14a–14h, and 16a–16e as
carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All
compounds were evaluated for inhibitory action against pharmacologically
relevant human CA isoforms I, II, IV, and VII. Compounds 11a–11g emerged as potent CA inhibitors against the four tested isoforms
with a significant selectivity to CA II, which is implicated in glaucoma
(Ki in the range 0.36–6.9 nM).
X-ray crystallographic analysis of three compounds (11a, 11d, and 11g) bound to CA II showed the
validity of the adopted drug design strategy as specific moieties
within the ligand structure interacted directly with the hydrophobic
and hydrophilic halves of the CA II active site. Compounds 11b–11d and 11g were evaluated for
their intraocular pressure-lowering effects in a rabbit model of glaucoma. 11b and 11d showed significant efficacy when
compared to the clinically used drug dorzolamide.