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

• Published in: European journal of medicinal chemistry Vol. 34; no. 10; pp. 799 - 808
• Main Authors: Supuran, Claudiu T, Scozzafava, Andrea, Menabuoni, Luca, Mincione, Francesco, Briganti, Fabrizio, Mincione, Giovanna
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Masson SAS 01-10-1999; Elsevier
• Subjects: antiglaucoma drugs; aromatic, heterocyclic sulfonamides; Biological and medical sciences; carbonic anhydrase; dorzolamide; Eye; hydrochloride salts; Medical sciences; nicotinoyl chloride; Pharmacology. Drug treatments; carbonic anhydrase; dorzolamide; antiglaucoma drugs; hydrochloride salts; nicotinoyl chloride; aromatic, heterocyclic sulfonamides; Antiglaucomatous agent; Five membered ring; Nitrogen heterocycle; Rabbit; Lyases; Thiadiazole derivatives; Pyridine derivatives; Eye; Local administration; Structure activity relation; Six membered ring; Chemical synthesis; Sulfur nitrogen heterocycle; Sulfonamide; Enzyme; Dorzolamide; Enzyme inhibitor; Lagomorpha; Water soluble compound; Vertebrata; Mammalia; Animal; Distribution; Carbonate dehydratase; Pharmacokinetics; Carbon-oxygen lyases; Topical administration; Hydro-lyases
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(99)00212-3

Reaction of twenty aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with nicotinoyl chloride afforded a series of water-soluble (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 nanomolar range), two isozymes known to play a critical role in aqueous humour 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 for many of them, and the active drug was detected in eye tissues and fluids. This result prompted us to re-analyse the synthetic work done 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 sulfonamido group is grafted, we also prepared a dorzolamide derivative to which the nicotinoyl moiety was attached. This new compound is more water soluble than dorzolamide (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 sulfonamido moiety is grafted.