Carbonic anhydrase inhibitors: Synthesis and inhibition against isozymes I, II and IV of topically acting antiglaucoma sulfonamides incorporating cis-5-norbornene-endo-3-carboxy-2-carboxamido moieties

Sulfonamides incorporating cis-5-norbornene-endo3-carboxy-2-carboxamido moi eties in their molecules were prepared by reaction of cis-5-norbornen-endo- 2,3-dicarboxylicanhydride with aromatic/heterocyclic sulfonamides possessin g free amino, hydrazino, or imino groups. Some of these compounds showed ve ry good CA II and CA IV inhibitory properties, with affinities for the enzy mes in the low nanomolar range. Some of the most active CA II inhibitors re ported here have been formulated as aqueous solutions for topical administr ation as antiglaucoma agents in normotensive rabbits. Some of the derivativ es incorporating cis-5-norbornene-endo-9-carboxy-2-carboxamido and aromatic sulfonamide moieties [as sodium salts) showed effective and longer lasting intraocular pressure (IOP) lowering as compared to dorzolamide, a widely u sed topical antiglaucoma drug. Compounds incorporating cis-5-norborneneendo -2,3-carboximido moieties, although stronger in vitro CA inhibitors as comp ared to the corresponding cis-5-norbomene-cndo-3-carboxy-2-carboxamido-deri vatives, showed no topical IOP lowering properties, probably due to their v ery poor water solubility.