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.
Maryanoff
Bruce E
BE
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA. bmaryano@prdus.jnj.com
McComsey
David F
DF
Costanzo
Michael J
MJ
Hochman
Coralie
C
Smith-Swintosky
Virginia
V
Shank
Richard P
RP
D000138:Acidosis / Q000139:chemically induced; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024402:Carbonic Anhydrase II / Q000737:chemistry / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005632:Fructose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013451:Sulfonic Acids / Q000737:chemistry*; D000077236:Topiramate
D000927:Anticonvulsants; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids; D000077236:Topiramate; D005632:Fructose; C005741:sulfamic acid; D024402:Carbonic Anhydrase II