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Abstract #15534 Published in IGR 1-3
Carbonic anhydrase inhibitors - Part 70. Synthesis and ocular pharmacology of a new class of water-soluble, topically effective intraocular pressure lowering agents derived from nicotinic acid and aromatic/heterocyclic sulfonamides
Supuran CT; Scozzafava A; Menabuoni L; Mincione F; Briganti F; Mincione GEuropean Journal of Medicinal Chemistry 1999; 34: 799-808
The reaction of 20 aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, to nicotinoyl chloride afforded a series of water-soluble (such as hydrochloride or triflate salts) compounds. The new derivatives were assayed as inhibitors of three carbonic anhydrase (CA) isozymes, hCA I, hCA II (cytosolic forms), and bCA IV (membrane-bound form); h: human, b: bovine isozyme. Efficient inhibition was observed against all three isozymes, but especially against hCA II and bCA IV (in the nanomolar range), 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 directly into the eye of normotensive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP) lowering was observed in many of them, and the active drug was detected in eye tissues and fluids. This result prompted the authors to re-analyze the synthetic work carried out by other groups for the design of water soluble, topically effective, antiglaucoma sulfonamides. According to these researchers, the IOP lowering effect is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sulfonamide derivatives represent the best studied case. Indeed, the first agents developed for such applications, such as dorzolamide, are derivatives of this ring system. In order to prove that the tail (in this case the nicotinoyl moiety) conferring water solubility to a sulfonamide CA inhibitor is critically important, similarly to the ring to which the sulfonamide group is grafted, the authors also prepared a dorzolamide derivative to which the nicotinoyl moiety was attached. This new compound is more water soluble than dorzolamide (such as hydrochloride salt), behaves as a strong CA II inhibitor, and acts similarly to the parent derivative in lowering IOP in experimental animals. Thus, it seems that the tail conferring water solubility is more important for topical activity as an antiglaucoma drug than the heterocyclic/aromatic ring to which the sulfonamide moiety is grafted.
Dr. C.T. Supuran, Universita degli Studi, Lab. Chim. Inorganica/Bioinorganica, Via Gino Capponi 7, I-50121 Firenze; Italy
Classification:
11.5.2 Topical (Part of: 11 Medical treatment > 11.5 Carbonic anhydrase inhibitors)
