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-Gl y (Sar sarcosine, N-Me-Gly; Crt = creatine, N-amidinosarcosine; TrS = trity lsulfenyl; Boc = tert-butoxycarbonyl) in the presence of carbodiimide deriv atives afforded after removal of the protecting groups a series of water-so luble compounds (as salts of strong acids, such as hydrochloric, trifluoroa cetic, or trifluoromethanesulfonic). The new derivatives were assayed as in hibitors of the zinc enzyme carbonic anhydrase (CA) and more precisely of t hree of its isozymes, CA I, II (cytosolic forms), and IV (membrane-bound fo rm), involved in important physiological processes. Efficient inhibition wa s observed against all three isozymes and especially against CA II and TV ( 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 th e best inhibitors synthesized were applied as 2% water solutions into the e ye of normotensive or glaucomatous albino rabbits, when strong and long-las ting intraocular pressure (IOP) lowering was observed with many of them. Th us, theaminoacyl/dipeptidyl tail conferring water solubility to these sulfo namide CA inhibitors coupled with strong enzyme inhibitory properties and b alanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity.