article · Journal of Medicinal Chemistry
Researchers have designed three series of dual-tailed sulfonamide compounds aimed at inhibiting carbonic anhydrase enzymes. Evaluation against human carbonic anhydrase isoforms I, II, IV, and VII identified one series, designated 11a to 11g, as particularly potent inhibitors. These compounds demonstrated notable selectivity for the isoform carbonic anhydrase II, an enzyme implicated in glaucoma, with inhibition constants ranging between 0.36 and 6.9 nanomolar. Structural analysis using X-ray crystallography confirmed that compounds from this series successfully engaged both the hydrophobic and hydrophilic regions of the enzyme active site. When tested in a rabbit model of glaucoma, selected compounds effectively lowered intraocular pressure. In particular, two candidates, 11b and 11d, showed significant therapeutic efficacy when compared against the established clinical drug dorzolamide, supporting the validity of this dual-tailed design strategy for ophthalmic drug discovery.
Glaucoma is a major condition characterised by increased pressure inside the eye, which can lead to vision loss if untreated. Current therapies often rely on inhibiting carbonic anhydrase enzymes to reduce this pressure. Discovering more selective and potent inhibitors offers potential opportunities to improve glaucoma treatment outcomes and develop more effective alternatives to existing clinical drugs.
This research demonstrates an early-stage therapeutic application for treating glaucoma. Targeted at pharmaceutical developers seeking improved ophthalmic treatments, the work has progressed through structural validation to preclinical testing in an animal model. Because testing remains at the animal study stage, the candidate molecules require extensive further preclinical safety, formulation, and clinical trials before any real-world commercial use is possible.
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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><sub>i</sub> 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.
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DOI: 10.1021/acs.jmedchem.9b02090
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