Carbonic anhydrase inhibitors: SAR and X-ray crystallographic study for the interaction of sugar sulfamates/sulfamides with isozymes I, II and IV.

Article Details

Citation

Casini A, Antel J, Abbate F, Scozzafava A, David S, Waldeck H, Schafer S, Supuran CT

Carbonic anhydrase inhibitors: SAR and X-ray crystallographic study for the interaction of sugar sulfamates/sulfamides with isozymes I, II and IV.

Bioorg Med Chem Lett. 2003 Mar 10;13(5):841-5.

PubMed ID
12617904 [ View in PubMed
]
Abstract

A series of sugar sulfamate/sulfamide derivatives were prepared and assayed as inhibitors of three carbonic anhydrase (CA) isozymes, hCA I, hCA II and bCA IV. Best inhibitory properties were observed for the clinically used antiepileptic drug topiramate, which is a low nanomolar CA II inhibitor, and possesses good inhibitory properties against the other two isozymes investigated here, similarly with acetazolamide, methazolamide or dichlorophenamide. The X-ray structure of the complex of topiramate with hCA II has been solved and it revealed a very tight association of the inhibitor, with a network of seven strong hydrogen bonds fixing topiramate within the active site, in addition to the Zn(II) coordination through the ionized sulfamate moiety. Structural changes in this series of sugar derivatives led to compounds with diminished CA inhibitory properties as compared to topiramate.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
TopiramateCarbonic anhydrase 2ProteinHumans
Yes
Inhibitor
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AcetazolamideCarbonic anhydrase 1Ki (nM)250N/AN/ADetails
AcetazolamideCarbonic anhydrase 2Ki (nM)12N/AN/ADetails
DiclofenamideCarbonic anhydrase 1Ki (nM)1200N/AN/ADetails
DiclofenamideCarbonic anhydrase 2Ki (nM)38N/AN/ADetails
EthoxzolamideCarbonic anhydrase 1Ki (nM)25N/AN/ADetails
EthoxzolamideCarbonic anhydrase 2Ki (nM)8N/AN/ADetails
TopiramateCarbonic anhydrase 1Ki (nM)250N/AN/ADetails
TopiramateCarbonic anhydrase 2Ki (nM)5N/AN/ADetails