Carbonic anhydrase inhibitors - part 78(#). Synthesis of water-soluble sulfonamides incorporating beta-alanyl moieties, possessing long lasting-intraocular pressure lowering properties via the topical route.
Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino or hydroxyl groups with N-tert-butyloxycarbonyl-beta-alanine (Boc-beta-ala; Boc = t-butoxycarbonyl) in the presence of carbodiimide derivatives afforded, after removal of the protecting group, a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic or trifluoromethane sulfonic). The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of three of its isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form), involved in important physiological processes. Good inhibition was observed against all three isozymes, but especially against CA II and CA IV (in the nanomolar range), the two isozymes known to play a critical role in aqueous humour secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% aqueous solutions into the eyes of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. Thus, the amino acyl groups conferring water solubility to these sulfonamide CA inhibitors, coupled with their strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity.
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Università degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Via Gino Capponi 7, I-50121, Florence, Italy. cts@bio.chim.unifi.it
Briganti
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Mincione
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Mincione
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Scozzafava
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D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003315:Cornea / Q000378:metabolism; D018360:Crystallography, X-Ray; D005123:Eye / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008968:Molecular Conformation; D011817:Rabbits; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D014867:Water
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; D014867:Water; D000409:Alanine