Carbonic anhydrase inhibitors. The mitochondrial isozyme VB as a new target for sulfonamide and sulfamate inhibitors.
Article Details
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Nishimori I, Vullo D, Innocenti A, Scozzafava A, Mastrolorenzo A, Supuran CT
Carbonic anhydrase inhibitors. The mitochondrial isozyme VB as a new target for sulfonamide and sulfamate inhibitors.
J Med Chem. 2005 Dec 1;48(24):7860-6.
- PubMed ID
- 16302824 [ View in PubMed]
- Abstract
A lately discovered carbonic anhydrase (hCA, EC 4.2.1.1), the mitochondrial hCA VB, was cloned, expressed, and purified. Kinetic parameters proved it to be 3.37 times more effective than hCA VA as a catalyst for the physiological reaction, with kcat = 9.5 x 10(5) s(-1) and kcat/K(M) = 9.8 x 10(7) M(-1) s(-1), being second only to hCA II among the 16 isoforms presently known in humans. We investigated the inhibition of hCA VB with a library of sulfonamides/sulfamates, some of which are clinically used compounds. Benzenesulfonamides were ineffective inhibitors, whereas derivatives bearing 4-amino, 4-hydrazino, 4-methyl, 4-carboxy moieties or halogenated sulfanilamides were more effective (Ki's of 1.56-4.3 microM). Among the 10 clinically used compounds, acetazolamide, benzolamide, topiramate, and indisulam showed effective inhibitory activity (Ki's of 18-62 nM). Three compounds showed better activity against hCA VB over hCA II, among which were sulpiride and ethoxzolamide, which were 2 times more effective inhibitors of the mitochondrial over the cytosolic isozyme. hCA VB is a druggable target and some of its inhibitors may lead to the development of novel antiobesity therapies.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 4-(2-AMINOETHYL)BENZENESULFONAMIDE Carbonic anhydrase 2 Ki (nM) 160 7.5 25 Details 5-(2-chlorophenyl)-1,3,4-thiadiazole-2-sulfonamide Carbonic anhydrase 2 Ki (nM) 12 7.5 25 Details 5-[(phenylsulfonyl)amino]-1,3,4-thiadiazole-2-sulfonamide Carbonic anhydrase 2 Ki (nM) 9 7.5 25 Details 6-HYDROXY-1,3-BENZOTHIAZOLE-2-SULFONAMIDE Carbonic anhydrase 2 Ki (nM) 30 7.5 25 Details Acetazolamide Carbonic anhydrase 2 Ki (nM) 12 7.5 25 Details Brinzolamide Carbonic anhydrase 2 Ki (nM) 3 7.5 25 Details Brinzolamide Carbonic anhydrase 5A, mitochondrial Ki (nM) 50 7.5 25 Details Diclofenamide Carbonic anhydrase 2 Ki (nM) 38 7.5 25 Details Dorzolamide Carbonic anhydrase 2 Ki (nM) 9 7.5 25 Details Ethoxzolamide Carbonic anhydrase 2 Ki (nM) 8 7.5 25 Details Methazolamide Carbonic anhydrase 2 Ki (nM) 14 7.5 25 Details Topiramate Carbonic anhydrase 2 Ki (nM) 10 7.5 25 Details