Carbonic anhydrase inhibitors: N-(p-sulfamoylphenyl)-alpha-D-glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits.
A series of N-(p-sulfamoylphenyl)-alpha-D-glycopyranosylamines was prepared by reaction of sulfanilamide with different monosaccharides in the presence of ammonium chloride. The new compounds were investigated for inhibition of the metallo-enzyme carbonic anhydrase (CA, EC 4.2.1.1), involved in aqueous humor secretion within the mammalian eye. Isozymes CA I and CA II were strongly inhibited by some of these compounds, which showed inhibition constants in the range of 510-1200 nM against CA I and 10-25 nM against CA II, similarly to clinically used sulfonamides, such as acetazolamide, methazolamide, dichlorophenamide, dorzolamide and brinzolamide. The presence of sugar moieties in these molecules induced an enhanced water solubility as compared to other sulfonamides. In hypertensive rabbits (a widely used animal model of glaucoma), two of the new compounds showed strong and long-lasting intraocular pressure (IOP) lowering, being more effective than dorzolamide and brinzolamide, the two clinically used, topically acting antiglaucoma sulfonamides with CA inhibitory properties.
Winum
Jean-Yves
JY
Université Montpellier II, Laboratoire de Chimie Biomoléculaire, UMR 5032, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.
Casini
Angela
A
Mincione
Francesco
F
Starnotti
Michele
M
Montero
Jean-Louis
JL
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D005901:Glaucoma / Q000188:drug therapy* / Q000201:enzymology; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology; D007429:Intraocular Pressure / Q000187:drug effects / Q000502:physiology; D008297:Male; D009005:Monosaccharides / Q000008:administration & dosage / Q000737:chemistry; D011817:Rabbits; D013424:Sulfanilamides / Q000008:administration & dosage / Q000737:chemistry
D000959:Antihypertensive Agents; D002257:Carbonic Anhydrase Inhibitors; D009005:Monosaccharides; D013424:Sulfanilamides