Carbonic anhydrase inhibitors: synthesis of water-soluble, aminoacyl/dipeptidyl sulfonamides 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 Boc-Gly, Boc-Sar, TrS-Crt, or Boc-Gly-Gly (Sar = sarcosine, N-Me-Gly; Crt = creatine, N-amidinosarcosine; TrS = tritylsulfenyl; Boc = tert-butoxycarbonyl) in the presence of carbodiimide derivatives afforded after removal of the protecting groups a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic, or trifluoromethanesulfonic). 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. Efficient inhibition was observed against all three isozymes and especially against CA II and IV (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 best inhibitors synthesized were applied as 2% water solutions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. Thus, the aminoacyl/dipeptidyl tail conferring water solubility to these sulfonamide CA inhibitors coupled with 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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Laboratorio di Chimica Inorganica e Bioinorganica, Università degli Studi, Via Gino Capponi 7, I-50121 Florence, Italy.
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D000287:Administration, Topical; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry; D002463:Cell Membrane Permeability; D003315:Cornea / Q000378:metabolism; D003692:Delayed-Action Preparations; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004195:Disease Models, Animal; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D011817:Rabbits; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013997:Time Factors
D002257:Carbonic Anhydrase Inhibitors; D003692:Delayed-Action Preparations; D004151:Dipeptides; D007527:Isoenzymes; D013449:Sulfonamides; D002256:Carbonic Anhydrases