title: Carbonic anhydrase inhibitors: sulfonamides incorporating furan-, thiophene- and pyrrole-carboxamido groups possess strong topical intraocular pressure lowering properties as aqueous suspensions.
abstract: Important physiological and physio-pathological functions are played by several carbonic anhydrase (CA, EC 4.2.1.1) isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides. Here we report several new types of such sulfonamides, incorporating furan-, thiophene- and pyrrole-carboxamide 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. in normotensive and glaucomatous rabbits. The derivatives incorporating furan- and pyrrole-carboxamide moieties (but not the corresponding thiophene-substituted derivatives), showed effective and long-lasting intraocular pressure (IOP) lowering both in normotensive as well as glaucomatous animals, with potencies superior to dorzolamide and brinzolamide, the two available topically acting sulfonamide drugs. This is the first example of non-water soluble sulfonamides that significantly lower IOP, being thus similar with the recently introduced drug brinzolamide, which belongs to a completely different chemical family of antiglaucoma sulfonamides.
authors.affiliation: University of Agricultural Sciences and Veterinary Medicine, Faculty of Biotechnologies, Department of Chemistry, Bucharest, Romania.
authors.forename: M
authors.initials: M
authors.lastname: Ilies
authors.forename: C T
authors.initials: CT
authors.lastname: Supuran
authors.forename: A
authors.initials: A
authors.lastname: Scozzafava
authors.forename: A
authors.initials: A
authors.lastname: Casini
authors.forename: F
authors.initials: F
authors.lastname: Mincione
authors.forename: L
authors.initials: L
authors.lastname: Menabuoni
authors.forename: M T
authors.initials: MT
authors.lastname: Caproiu
authors.forename: M
authors.initials: M
authors.lastname: Maganu
authors.forename: M D
authors.initials: MD
authors.lastname: Banciu
mesh_terms: D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism*; D002918:Chymotrypsin; D003315:Cornea / Q000503:physiopathology; D005901:Glaucoma / Q000188:drug therapy*; D006801:Humans; D007527:Isoenzymes; D008297:Male; D015394:Molecular Structure; D009798:Ocular Hypertension / Q000139:chemically induced / Q000188:drug therapy; D011817:Rabbits; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; D002256:Carbonic Anhydrases