Carbonic anhydrase inhibitors. Part 79. Synthesis of topically acting sulfonamides incorporating GABA moieties in their molecule, with long-lasting intraocular pressure-lowering properties.
Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino or hydroxyl groups with N-tert-butoxycarbonyl-gamma-aminobutyric acid (Boc-GABA; Boc=t-butoxycarbonyl) in the presence of carbodiimide derivatives, afforded after removal of the protecting group, a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic or trifluoromethane sulfonic). 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. Some of the new compounds effectively inhibited CA II and CA 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 obtained as described above were applied as 2% water solutions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering has been evidenced. Thus, the amino acyl tail conferring water solubility to these sulfonamides, coupled with their strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity from the class of the carbonic anhydrase inhibitors.
Mincione
G
G
Laboratorio di Chimica Inorganica e Bioinorganica, Università degli Studi, Via Gino Capponi 7, I-50121, Florence, Italy.
Menabuoni
L
L
Briganti
F
F
Mincione
F
F
Scozzafava
A
A
Supuran
C T
CT
D000287:Administration, Topical; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use*; D002462:Cell Membrane / Q000201:enzymology; D003315:Cornea / Q000502:physiology; D003600:Cytosol / Q000201:enzymology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000235:genetics; D005901:Glaucoma / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D010539:Permeability; D011817:Rabbits; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D013997:Time Factors; D014065:Tonometry, Ocular; D014867:Water / Q000737:chemistry; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; D014867:Water; D005680:gamma-Aminobutyric Acid