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

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.

Citation

Bruce E Maryanoff, David F McComsey, Michael J Costanzo, Coralie Hochman, Virginia Smith-Swintosky, Richard P Shank. Comparison of sulfamate and sulfamide groups for the inhibition of carbonic anhydrase-II by using topiramate as a structural platform. Journal of medicinal chemistry. 2005 Mar 24;48(6):1941-7

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PMID: 15771438

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