PubMed · 14201418
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H S SUGAR. 1964. GLAUCOMA AND THE PRACTITIONER.. https://pubmed.ncbi.nlm.nih.gov/14201418/
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AIM: To determine the value of a topical carbonic anhydrase inhibitor for extended treatment of cystoid macular oedema (CME) in patients with retinitis pigmentosa (RP). METHOD: Eight patients with RP and foveal cystic-appearing lesions observed on fundus examination and by optical coherence tomography (OCT) testing were treated with a topical form of carbonic anhydrase inhibitor. RESULTS: Foveal cystic-like spaces were documented by OCT testing in all eight patients before treatment. All patients had a significant reduction in their foveal thickness (FT) and foveal zone thickness (FZT) in at least one eye after using 2% dorzolamide three times a day for 1 or 2 months. Six patients had an improvement in both eyes. After an additional 6-13 months of the same treatment regimen, out of six patients who had a sustained reduction in FT and FZT in at least one eye, four had this reduction in both eyes. While they were still taking Trusopt, a recurrence (rebound) of CME in both eyes was observed in two patients, whereas one patient had a sustained improvement in one eye and rebound of CME in the other eye. Out of 8 patients, 3 showed an improvement in their visual acuity by > or =7 letters, in at least one eye, on Snellen acuity charts, which was determined as clinically significant. CONCLUSION: Results from this study suggest that patients with RP could potentially sustain a beneficial effect from continued treatment with a topical form of carbonic anhydrase inhibitor.
A library of glycoconjugate benzenesulfonamides that contain diverse carbohydrate-triazole tails were investigated for their ability to inhibit the enzymatic activity of the three human transmembrane carbonic anhydrase (CA) isozymes hCA IX, hCA XII and hCA XIV. These isozymes have their CA domains located extracellularly, unlike the physiologically dominant hCA II, and are of immense current interest as druggable targets. Elevated expression of isozymes IX and XII is a marker for a broad spectrum of hypoxic tumors-this physiology may facilitate a novel approach to discriminate between healthy cells and cancerous cells. Many of these glycoconjugates were potent inhibitors (low nM), but importantly exhibited different isozyme selectivity profiles. The most potent hCA IX inhibitor was the glucuronic acid derivative 20 (K(i)=23nM). This compound was uniquely hCA IX selective cf. all other isozymes (16.4-, 16.8- and 4.6-fold selective against hCA II, XII, and XIV, respectively). At hCA XII there were many inhibitors with K(i)s<10nM that also demonstrated excellent selectivity (up to 344-fold) against other isozymes. Potent hCA XIV inhibitors were also identified, several with K(i)s approximately 10nM, however no hCA XIV-selective derivatives were evidenced from this library. The sugar tails of this study have shown promise as a valuable approach to both solubilize the aromatic sulfonamide CA recognition pharmacophore and to deliver potent inhibition and isozyme differentiation of the transmembrane CAs.
The X-ray crystal structures of 5-amino-1,3,4-thiadiazole-2-sulfonamide (the acetazolamide precursor) and 5-(4-amino-3-chloro-5-fluorophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide in complex with the human isozyme II of carbonic anhydrase (CA, EC 4.2.1.1) are reported. The thiadiazole-sulfonamide moiety of the two compounds binds in the canonic manner to the zinc ion and interacts with Thr199, Glu106, and Thr200. The substituted phenyl tail of the second inhibitor was positioned in the hydrophobic part of the binding pocket, at van der Waals distance from Phe131, Val 135, Val141, Leu198, Pro202, and Leu204. These structures may help in the design of better inhibitors of these widespread zinc-containing enzymes.