Carbonic anhydrase inhibitors: Sulfonamides incorporating furan-, thiophene- and pyrrole-carboxamido groups possess strong topical intraocular pressure lowering properties as aqueous suspensions

Important physiological and physio-pathological functions are played by sev eral carbonic anhydrase (CAI EC 4.2.1.1) isozymes, which are strongly inhib ited by aromatic and heterocyclic sulfonamides. Here we report several new types of such sulfonamides, incorporating furan-, thiophene- and pyrrole-ca rboxamide moieties in their molecules. Some of these compounds showed very good CA II and CA IV inhibitory properties, with affinities for the enzymes in the low nanomolar range. Due to their relatively low water solubility, some of the most active CA II inhibitors reported here have been formulated as aqueous suspension for topical administration as antiglaucoma agents, i n normotensive and glaucomatous rabbits. The derivatives incorporating fura n- and pyrrole-carboxamide moieties (but not the corresponding thiophene-su bstituted derivatives), showed effective and long-lasting intraocular press ure (IOP) lowering both in normotensive as well as glaucomatous animals, wi th potencies superior to dorzolamide and brinzolamide, the two available to pically acting sulfonamide drugs. This is the first example of non-water so luble sulfonamides that significantly lower IOP, being thus similar with th e recently introduced drug brinzolamide, which belongs to a completely diff erent chemical family of antiglaucoma sulfonamides. (C) 2000 Elsevier Scien ce Ltd, All rights reserved.