SULFONYLMETHANESULFONAMIDE INHIBITORS OF CARBONIC-ANHYDRASE

A series of sulfonylmethanesulfonamide derivatives is described, which are inhibitors of carbonic anhydrase (CA). The most potent of these i s the racemic fluoro sulfone 9, which inhibits carbon dioxide hydratio n catalyzed by human CA II (CA-II) with an IC50 of 3 nM. Binding compe tition studies versus dansylamide indicate that the enantiomers of 9 h ave different affinities for CA-II, with equilibrium dissociation cons tants of 3.6 and 0.6 nM. QSAR analysis suggests that the key factors i nvolved in achieving high affinity in this series are sulfonamide acid ity, hydrophobicity, and minimization of steric demands at the carbon atom adjacent to the sulfonamide group.