Comparison of sulfamate and sulfamide groups for the inhibition of carbonic anhydrase-II by using topiramate as a structural platform.

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Maryanoff BE, McComsey DF, Costanzo MJ, Hochman C, Smith-Swintosky V, Shank RP

Comparison of sulfamate and sulfamide groups for the inhibition of carbonic anhydrase-II by using topiramate as a structural platform.

J Med Chem. 2005 Mar 24;48(6):1941-7.

PubMed ID

15771438 [ View in PubMed

]

Abstract

This paper examines the relative effectiveness of sulfamate and sulfamide groups for the inhibition of carbonic anhydrase-II (CA-II). Topiramate (1) and its sulfamide analogue 4, and 4,5-cyclic sulfate 6 and its sulfamide analogue 5, were compared for inhibition of human CA-II. A colorimetric assay, based on the pH shift that accompanies hydration of carbon dioxide, and an esterase assay were used. For these bioisosteric pairs, 1/4 and 6/5, the sulfamate compound was markedly more potent than its sulfamide counterpart. A similar, large difference in potency was also observed for the sulfamate/sulfamide pairs 14/15 and 16/17. These results indicate that the sulfamide moiety is not particularly suitable for obtaining potent carbonic anhydrase inhibition. A discussion of this structure-activity relationship with respect to the interactions of 1 and 6 with CA-II from published X-ray data is presented. A metabolic acidosis study was performed in rats with 1, 4, 6, and 2, and the results are discussed with respect to the degree of inhibition of CA-II in vivo.

DrugBank Data that Cites this Article

Drugs

Topiramate

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Topiramate	Carbonic anhydrase 2	Protein	Humans	Yes	Inhibitor	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Acetazolamide	Carbonic anhydrase 2	Ki (nM)	18	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 2	Ki (nM)	3.3	N/A	N/A	Details
Sulfamic Acid 2,3-O-(1-Methylethylidene)-4,5-O-Sulfonyl-Beta-Fructopyranose Ester	Carbonic anhydrase 2	Ki (nM)	38	N/A	N/A	Details
Sulfamic Acid 2,3-O-(1-Methylethylidene)-4,5-O-Sulfonyl-Beta-Fructopyranose Ester	Carbonic anhydrase 2	Ki (nM)	750	N/A	N/A	Details
Sulfamic Acid 2,3-O-(1-Methylethylidene)-4,5-O-Sulfonyl-Beta-Fructopyranose Ester	Carbonic anhydrase 2	Ki (nM)	910	N/A	N/A	Details
Sulfamic Acid 2,3-O-(1-Methylethylidene)-4,5-O-Sulfonyl-Beta-Fructopyranose Ester	Carbonic anhydrase 2	Ki (nM)	12	N/A	N/A	Details
Topiramate	Carbonic anhydrase 2	Ki (nM)	500	N/A	N/A	Details
Topiramate	Carbonic anhydrase 2	Ki (nM)	7700	N/A	N/A	Details
Topiramate	Carbonic anhydrase 2	Ki (nM)	430	N/A	N/A	Details
Topiramate	Carbonic anhydrase 2	Ki (nM)	9600	N/A	N/A	Details