Carbonic anhydrase inhibitors. Part 71 - Synthesis and ocular pharmacologyof a new class of water-soluble, topically effective intraocular pressure lowering sulfonamides incorporating picolinoyl moieties

Reaction of 20 aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with picolinic acid in the presence of carbodiimide derivatives afforded a series of water-soluble (as hydrochlori de or triflate salts) compounds. The new derivatives were assayed as inhibi tors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form). Efficient inhibition was observed against all three isozymes, but especially against CA II and CA IV (in nanomolar range ), the two isozymes known to play a critical role in aqueous humor secretio n within the ciliary processes of the eye. Some of the best inhibitors synt hesized were applied as 2% water solutions directly into the eye of normote nsive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP ) lowering was observed for many of them, and the active drug was detected in eye tissues and fluids. This result prompted us to reanalyze the synthet ic work done by other groups for the design of water soluble, topically eff ective antiglaucoma sulfonamides. According to these researchers, the IOP l owering effect is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-suIfonamide deriv atives represent the best studied case. Indeed, the first agents developed for such applications, such as dorzolamide, are derivatives of this ring sy stem. In order to prove that the tail (in this case the picolinoyl moiety) conferring water solubility to a sulfonamide CA inhibitor is critically imp ortant for its topical effectiveness, similarly to the ring to which the su lfonamido group is grafted, we also prepared a dorzolamide derivative to wh ich the picolinoyl moiety was attached. This new compound is more water sol uble than dorzolamide (as hydrochloride salt), behaves as a strong CA II in hibitor, and acts similarly to the parent derivative in lowering IOP in exp erimental animals. Thus, it seems that the tail conferring water solubility is more important for topical activity as antiglaucoma drug, than the hete rocyclic/aromatic ring to which the sulfonamido moiety is grafted. (C) 1999 Elsevier Science B.V. All rights reserved.