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

Abstract

The design of three dual-tailed sulfonamide series <b>11a-11g</b>, <b>14a-14h</b>, and <b>16a-16e</b> 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 <b>11a-11g</b> emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma (<i>K</i>_i in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (<b>11a</b>, <b>11d</b>, and <b>11g</b>) 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 <b>11b</b>-<b>11d</b> and <b>11g</b> were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. <b>11b</b> and <b>11d</b> showed significant efficacy when compared to the clinically used drug dorzolamide.