Carbonic anhydrase inhibitors: 2-substituted-1,3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes VA and VB over the cytosolic and membrane-associated carbonic anhydrases I, II and IV.
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Smaine FZ, Pacchiano F, Rami M, Barragan-Montero V, Vullo D, Scozzafava A, Winum JY, Supuran CT
Carbonic anhydrase inhibitors: 2-substituted-1,3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes VA and VB over the cytosolic and membrane-associated carbonic anhydrases I, II and IV.
Bioorg Med Chem Lett. 2008 Dec 15;18(24):6332-5. doi: 10.1016/j.bmcl.2008.10.093. Epub 2008 Nov 1.
- PubMed ID
- 18990571 [ View in PubMed]
- Abstract
A series of 2-substituted-1,3,4-thiadiazole-5-sulfamides was prepared and assayed as inhibitors of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, the membrane-associated CA IV and the mitochondrial CA VA and VB. The new compounds showed weak inhibitory activity against hCA I (K(I)s of 102 nM-7.42 microM), hCA II (K(I)s of 0.54-7.42 microM) and hCA IV (K(I)s of 4.32-10.05 microM) but were low nanomolar inhibitors of hCA VA and hCA VB, with inhibition constants in the range of 4.2-32 nM and 1.3-74 nM, respectively. Furthermore, the selectivity ratios for inhibiting the mitochondrial enzymes over CA II were in the range of 67.5-415, making these sulfamides the first selective CA VA/VB inhibitors.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Acetazolamide Carbonic anhydrase 1 Ki (nM) 250 N/A N/A Details Acetazolamide Carbonic anhydrase 2 Ki (nM) 12 N/A N/A Details Acetazolamide Carbonic anhydrase 4 Ki (nM) 74 N/A N/A Details Topiramate Carbonic anhydrase 1 Ki (nM) 250 N/A N/A Details Topiramate Carbonic anhydrase 2 Ki (nM) 10 N/A N/A Details Topiramate Carbonic anhydrase 4 Ki (nM) 4900 N/A N/A Details Zonisamide Carbonic anhydrase 1 Ki (nM) 56 N/A N/A Details Zonisamide Carbonic anhydrase 2 Ki (nM) 35 N/A N/A Details Zonisamide Carbonic anhydrase 4 Ki (nM) 8590 N/A N/A Details Zonisamide Carbonic anhydrase 5A, mitochondrial Ki (nM) 20000 N/A N/A Details Zonisamide Carbonic anhydrase 5B, mitochondrial Ki (nM) 6033000 N/A N/A Details