Carbonic Anhydrase Inhibitors:  Synthesis and Topical Intraocular Pressure Lowering Effects of Fluorine-Containing Inhibitors Devoid of Enhanced Reactivity

Abstract

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.

A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology

“…NCX250 is a potent inhibitor of CA II, IV and XII (K I s of 18-44 nM 7 ), all isoforms involved in aqueous humour secretion within the eye 2, 15,16 . DRZ is a more potent CA II and XII inhibitor than NCX250 (K I s of 9 and 3.5 nM, respectively), but acts as a rather weak CA IV inhibitor (K I of 8.5 µM 10,24 ).…”

“…intramuscularly 14 . IOP was measured before carbomer injection and after 1, 2 and 4 h the first day and three times a day until stabilization 15,16 and then every 24 h. All rabbits treated with carbomer presented a net increase in IOP. One drop of 0.2% oxybuprocaine hydrochloride (Novesine, Sandoz) diluted 1:1 with sterile saline was instilled in each eye immediately before each set of pressure measurements.…”

“…IOP was measured using a Tono-Pen XL tonometer (Medtronic Solan, Jacksonville, FL) as reported by earlier 15,16 . The pressure readings were matched with twopoint standard pressure measurements every week using a Digilab calibration verifier.…”

Multiple Binding Modes of Inhibitors to Carbonic Anhydrases: How to Design Specific Drugs Targeting 15 Different Isoforms?

“…5,200,206 To modify the hydrophilic character and the lack of water/lipid solubility of 65, some derivatives incorporating polyhalophenylsulfonamide moieties instead of phenylsulfonamide were investigated (see compound 60 as an example). 118,202,207 These compounds generally retained the excellent inhibitory properties of the lead compound, but at the same time possessed much higher solubility both in water and in organic solvents, as well as better penetrability through biological membranes. 197 Several structural studies on the complexes that these heterocyclic bis-sulfonamides form with hCA II are so far available.…”

Modelling the inhibition activity on carbonic anhydrase I of some substituted thiadiazole- and thiadiazoline-disulfonamides: integration of structure information

“…There are known in human eleven active CA isozymes [2], some of which act in cytosol (I, II and III), others being membrane-bound isozymes (IV, VII, IX, XII and XIV), mitochondrial isozyme (V), and one secreted salivary isozyme (VI). The carbonic anhydrase I it is known to has low catalytic activity comparing with carbonic anhydrase II [3] and medium affinity for sulfonamides [4]. 1,3,4-Thiadiazole-and 1,3,4-Thiadiazoline-Disulfonamides played an important role in development of classes of pharmacological agents based on their biological action of inhibition of the carbonic anhydrases enzymes [5].…”