title: Sulfonylmethanesulfonamide inhibitors of carbonic anhydrase.
abstract: A series of sulfonylmethanesulfonamide derivatives is described, which are inhibitors of carbonic anhydrase (CA). The most potent of these is the racemic fluoro sulfone 9, which inhibits carbon dioxide hydration catalyzed by human CA II (CA-II) with an IC50 of 3 nM. Binding competition studies versus dansylamide indicate that the enantiomers of 9 have different affinities for CA-II, with equilibrium dissociation constants of 3.6 and 0.6 nM. QSAR analysis suggests that the key factors involved in achieving high affinity in this series are sulfonamide acidity, hydrophobicity, and minimization of steric demands at the carbon atom adjacent to the sulfonamide group.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: T H
authors.initials: TH
authors.lastname: Scholz
authors.forename: J M
authors.initials: JM
authors.lastname: Sondey
authors.forename: W C
authors.initials: WC
authors.lastname: Randall
authors.forename: H
authors.initials: H
authors.lastname: Schwam
authors.forename: W J
authors.initials: WJ
authors.lastname: Thompson
authors.forename: P J
authors.initials: PJ
authors.lastname: Mallorga
authors.forename: M F
authors.initials: MF
authors.lastname: Sugrue
authors.forename: S L
authors.initials: SL
authors.lastname: Graham
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides