title: Carbonic anhydrase inhibition. Insight into the characteristics of zonisamide, topiramate, and the sulfamide cognate of topiramate.
abstract: Some useful therapeutic agents inhibit certain carbonic anhydrase (CA) isozymes to varying degrees. We have conducted enzyme kinetics studies in a 4-nitrophenyl acetate (4-NPA) hydrolysis assay with the marketed antiepileptic drugs topiramate (1) and zonisamide (2) to determine if their full inhibition of human CA-II and CA-I requires extended preincubation conditions. We found that neither 1 nor 2 requires appreciable preincubation with either enzyme to manifest full inhibitory activity. We also examined the sulfamide cognate of topiramate (3) to characterize its CA inhibitory activity, and confirmed that it is a very weak inhibitor, unlike 1 or 2. In a CO(2) hydration assay, 3 behaved as a very weak, partial inhibitor of CA-II and CA-I. We conclude that topiramate (1), zonisamide (2), and sulfamide 3 do not require extended exposure to human CA-I or CA-II to manifest full inhibitory activity (4-NPA assay).
authors.affiliation: Research & Early Development, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. richardshank@comcast.net
authors.forename: Richard P
authors.initials: RP
authors.lastname: Shank
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Smith-Swintosky
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D005632:Fructose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry*; D000077236:Topiramate; D000078305:Zonisamide
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007555:Isoxazoles; D013449:Sulfonamides; D000077236:Topiramate; D005632:Fructose; D000078305:Zonisamide; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II