Carbonic anhydrase inhibitors: synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity.
Polyfluorinated carbonic anhydrase inhibitors (CAIs) show very good inhibitory properties against carbonic anhydrase (CA) and excellent in vivo antiglaucoma properties after topical administration in rabbits. Still, the pentafluorinated compounds reported previously by this group (Scozzafava et al. J. Med. Chem. 2000, 43, 4542-4551) showed high reactivity with thiol groups of cysteine, glutathione, and presumably other proteins containing such moieties, which may lead to severe ocular side effects. Here, we report an approach for obtaining fluorinated CA inhibitors without the undesired enhanced reactivity. Thus, new compounds have been obtained by attaching moieties with reduced reactivity toward aromatic substitution reactions to the molecules of aromatic/heterocyclic sulfonamides possessing derivatizable amino moieties. The employed tails of the 2,3,5,6-tetrafluorobenzoyl, 2,3,5,6-tetrafluophenylsulfonyl, and pentafluorophenylureido types induced excellent CA inhibitory properties in the new reported sulfonamides, mainly against the isozymes involved in aqueous humor secretion, CA II and CA IV, whereas affinity for CA I was lower. Several low-nanomolar CA II inhibitors were detected, which did not react with cysteine or glutathione, in contrast to the corresponding perfluorinated compounds previously reported. These derivatives also showed a potent reduction of the intraocular pressure (IOP) in hypertensive rabbits, amounting to 13-21 mmHg at 1 h postadministration (compared to 5 mmHg obtained with dorzolamide, a clinically used drug), and the decreased IOP was maintained for 4-5 h after the administration. These compounds constitute valuable candidates for obtaining topically acting antiglaucoma CA inhibitors of a new generation, with enhanced efficacy, prolonged duration of action, and reduced side effects.
de Leval
Xavier
X
Natural and Synthetic Drug Research Center, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
Ilies
Monica
M
Casini
Angela
A
Dogné
Jean-Michel
JM
Scozzafava
Andrea
A
Masini
Emanuela
E
Mincione
Francesco
F
Starnotti
Michele
M
Supuran
Claudiu T
CT
D000287:Administration, Topical; D000818:Animals; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D030741:Carbonic Anhydrase IV / Q000037:antagonists & inhibitors; D002257:Carbonic Anhydrase Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D005461:Fluorine; D005901:Glaucoma / Q000188:drug therapy / Q000503:physiopathology; D006571:Heterocyclic Compounds / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D006571:Heterocyclic Compounds; D013449:Sulfonamides; C061891:thiahexatroxane; D005461:Fluorine; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D030741:Carbonic Anhydrase IV