title: Carbonic anhydrase inhibitors. Water-soluble, topically effective intraocular pressure lowering agents derived from isonicotinic acid and aromatic/heterocyclic sulfonamides: is the tail more important than the ring?
abstract: Reaction of twenty aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with isonicotinoyl chloride afforded a series of water-soluble compounds (as hydrochloride or triflate salts). The new derivatives were examined as inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form). Efficient inhibition was observed against all three isozymes, but especially against CA II and CA IV (K(I) in the nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the most potent inhibitors synthesized were applied as 2% water solutions directly into the eye of normotensive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP) lowering was observed for many of them, and the active drug was detected in eye tissues and fluids. According to others the IOP lowering effect of topically effective antiglaucoma sulfonamides is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sulfonamide derivatives represent the best studied case e.g. dorzolamide. In order to prove that the tail (in this case the isonicotinoyl moiety) conferring water solubility to a sulfonamide CA inhibitor is more important than the ring to which the sulfonamido group is grafted a dorzolamide derivative to which the isonicotinoyl moiety was attached was also prepared. This new compound is more water soluble than dorzolamide (as hydrochloride salt), behaves as a strong CA II inhibitor and acts similarly to the parent derivative in lowering IOP in experimental animals. Thus, it seems that the tail conferring water solubility is more important for topical activity as an antiglaucoma drug than the heterocyclic/aromatic ring to which the sulfonamido moiety is attached.
authors.affiliation: Ospedale San Giovanni di Dio, U.O. Oculistica, Firenze, Italia.
authors.forename: L
authors.initials: L
authors.lastname: Menabuoni
authors.forename: A
authors.initials: A
authors.lastname: Scozzafava
authors.forename: F
authors.initials: F
authors.lastname: Mincione
authors.forename: F
authors.initials: F
authors.lastname: Briganti
authors.forename: G
authors.initials: G
authors.lastname: Mincione
authors.forename: C T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism; D005123:Eye / Q000187:drug effects / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy; D006571:Heterocyclic Compounds; D006801:Humans; D006841:Hydrocarbons, Aromatic; D007429:Intraocular Pressure / Q000187:drug effects; D007539:Isonicotinic Acids / Q000378:metabolism; D011817:Rabbits; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D006571:Heterocyclic Compounds; D006841:Hydrocarbons, Aromatic; D007539:Isonicotinic Acids; D013449:Sulfonamides; D002256:Carbonic Anhydrases