Carbonic anhydrase inhibitors: design of thioureido sulfonamides with potent isozyme II and XII inhibitory properties and intraocular pressure lowering activity in a rabbit model of glaucoma.
A new series of thioureido-substituted sulfonamides were prepared by reacting 4-isothiocyanato- or 4-isothiocyanatoethyl-benzenesulfonamide with amines, hydrazines, or amino acids bearing moieties that can lead to an enhanced hydrosolubility, such as 2-dimethylamino-ethylamine, fluorine-containing aromatic amines/hydrazines, an aminodiol, heterocyclic polyamines (derivatives of morpholine and piperazine), 4-aminobenzoic acid, or natural amino acids (Gly, Cys, Asn, Arg, and Phe). The new compounds showed good inhibitory properties against three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, with K(I)s in the range of 24-324 nM against the cytosolic isoform CA I, of 6-185 nM against the other cytosolic isozyme CA II, and of 1.5-144 nM against the transmembrane isozyme CA XII. Some of the new derivatives were also very effective in reducing elevated intraocular pressure in hypertensive rabbits as a glaucoma animal model. Considering that this is the first study in which potent CA II/CA XII inhibitors are designed and investigated in vivo, it may be assumed that the target isozymes of the antiglaucoma sulfonamides are indeed the cytosolic CA II and the transmembrane CA XII.
Mincione
Francesco
F
U.O. Oculistica Az. USL 3, Val di Nievole, Ospedale di Pescia, Pescia, Italy.
Starnotti
Michele
M
Masini
Emanuela
E
Bacciottini
Lucia
L
Scrivanti
Chiara
C
Casini
Angela
A
Vullo
Daniela
D
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000818:Animals; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000187:drug effects; D004195:Disease Models, Animal; D015195:Drug Design; D005901:Glaucoma / Q000188:drug therapy*; D007429:Intraocular Pressure / Q000187:drug effects*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII