Carbonic Anhydrase Inhibitors:  Synthesis of Water-Soluble, Aminoacyl/Dipeptidyl Sulfonamides Possessing Long-Lasting Intraocular Pressure-Lowering Properties via the Topical Route

• Published in: Journal of medicinal chemistry Vol. 42; no. 18; pp. 3690 - 3700
• Main Authors: Scozzafava, Andrea, Briganti, Fabrizio, Mincione, Giovanna, Menabuoni, Luca, Mincione, Francesco, Supuran, Claudiu T
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.09.1999; Amer Chemical Soc
• Subjects: Administration, Topical; Animals; Biological and medical sciences; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - chemistry; Cell Membrane Permeability; Chemistry, Medicinal; Cornea - metabolism; Delayed-Action Preparations; Dipeptides - chemical synthesis; Dipeptides - pharmacology; Disease Models, Animal; Eye; Glaucoma - drug therapy; Humans; Intraocular Pressure - drug effects; Isoenzymes - antagonists & inhibitors; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rabbits; Science & Technology; Solubility; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Time Factors; SPECTROSCOPIC INVESTIGATIONS; AROMATIC SULFONAMIDES; SULFENAMIDO-SULFONAMIDES; BINDING CONSTANTS; ISOZYME-II; OCULAR HYPOTENSIVE ACTIVITY; GLAUCOMA; IV; DERIVATIVES; METAL-COMPLEXES; Antiglaucomatous agent; Cornea; Five membered ring; Isozyme; Rabbit; Lyases; Selectivity; Thiadiazole derivatives; Local administration; Absorption; Structure activity relation; Glaucoma (eye); Chemical synthesis; Sulfur nitrogen heterocycle; Sulfonamide; Enzyme; Enzyme inhibitor; Guanidines; Lagomorpha; In vitro; Water soluble compound; In vivo; Vertebrata; Ophthalmic preparation; Eye disease; Mammalia; Penetration; Animal; Carboxamide; Carbonate dehydratase; Pharmacokinetics; Carbon-oxygen lyases; Topical administration; Hydro-lyases; Duration of action
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9901879

Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino, or hydroxyl groups with Boc-Gly, Boc-Sar, TrS-Crt, or Boc-Gly-Gly (Sar = sarcosine, N-Me-Gly; Crt = creatine, N-amidinosarcosine; TrS = tritylsulfenyl; Boc = tert-butoxycarbonyl) in the presence of carbodiimide derivatives afforded after removal of the protecting groups a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic, or trifluoromethanesulfonic). The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA) and more precisely of three of its isozymes, CA I, II (cytosolic forms), and IV (membrane-bound form), involved in important physiological processes. Efficient inhibition was observed against all three isozymes and especially against CA II and IV (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 the best inhibitors synthesized were applied as 2% water solutions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. Thus, the aminoacyl/dipeptidyl tail conferring water solubility to these sulfonamide CA inhibitors coupled with strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity.