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 derivati ves afforded, after removal of the protecting group, a series of water-solu ble compounds (as salts of strong acids, such as hydrochloric, trifluoroace tic or trifluoromethane sulfonic). The new derivatives were assayed as inhi bitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of th ree of its isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form ), involved in important physiological processes. Good inhibition was obser ved 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 aqu eous humour secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% aqueous solutions into the e yes of normotensive or glaucomatous albino rabbits, when strong and long-la sting intraocular pressure (IOP) lowering was observed with many of them. T hus, 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 compound s with effective topical antiglaucoma activity. (C) 2000 Editions scientifi ques et medicales Elsevier SAS.