title: The anticonvulsant sulfamide JNJ-26990990 and its S,S-dioxide analog strongly inhibit carbonic anhydrases: solution and X-ray crystallographic studies.
abstract: JNJ-26990990 ((benzo[b]thien-3-yl)methyl)sulfamide, a sulfamide derivative structurally related to the antiepileptic drug zonisamide, was reported to be devoid of carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties. Here we report that JNJ-26990990 and its S,S-dioxide analog significantly inhibit six human (h) isoforms, hCA I, II, VII, IX, XII and XIV, involved in crucial physiological processes. Inhibition and X-ray crystallographic data for the binding of the two compounds to these enzymes show significant similarity with the zonisamide inhibitory pattern. These findings prompted us to reconsider the structural/pharmacological requirements for designing effective antiepileptics possessing zinc-binding groups of the sulfamide, sulfamate or sulfonamide type in their molecules.
authors.affiliation: Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Napoli, Italy. gdesimon@unina.it claudiu.supuran@unifi.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Fiore
authors.forename: Giuseppina
authors.initials: G
authors.lastname: De Simone
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Alterio
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Riccio
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D010087:Oxides / Q000737:chemistry*; D011487:Protein Conformation; D012996:Solutions; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D013455:Sulfur / Q000737:chemistry*; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D002257:Carbonic Anhydrase Inhibitors; D010087:Oxides; D012996:Solutions; D013449:Sulfonamides; D013876:Thiophenes; D013455:Sulfur; D002256:Carbonic Anhydrases; C545991:N-((benzo(b)thien-3-yl)methyl)sulfamide