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?

Reaction of twenty aromatic/heterocyclic sulfonamides containing a free ami no, imino, hydrazino or hydroxyl group, with isonicotinoyl chloride afforde d a series of water-soluble compounds (as hydrochloride or triflate salts). The new derivatives were examined as inhibitors of three carbonic anhydras e (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form). E fficient inhibition was observed against all three isozymes, but especially against CA II and CA IV (K-I in the nanomolar range), the two isozymes kno wn to play a critical role in aqueous humor secretion within the ciliary pr ocesses of the eye. Some of the most potent inhibitors synthesized were app lied as 2% wards solutions directly into the eye of normotensive or glaucom atous albino rabbits. Very strong intraocular pressure (IOP) lowering was o bserved for many of them, and the active drug was detected in eye tissues a nd fluids. According to others the IOP lowering effect of topically effecti ve antiglaucoma sulfonamides is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sul fonamide derivatives represent the best studied case e.g. dorzolamide. In o rder to prove that the tail (in this case the isonicotinoyl moiety) conferr ing water solubility to a sulfonamide CA inhibitor is more important than t he 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), b ehaves as a strong CA II inhibitor and acts similarly to the parent derivat ive in lowering IOP in experimental animals. Thus, it seems that the tail c onferring water solubility is more important for topical activity as an ant iglaucoma drug than the heterocyclic/aromatic ring to which the sulfonamido moiety is attached.