6-hydroxybenzothiazide-2-sulfonamide and Glaucoma

The inhibition of a newly cloned human carbonic anhydrase (CA, EC 4.2.1.1), isozyme XII (hCA XII), has been investigated with a series of sulfonamides, including some clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and sulpiride, or indisulam, a compound in clinical development as antitumor drug), as well as the sulfamate antiepileptic drug topiramate. Some simple amino-/hydrazine-/hydroxy-substituted aromatic/heterocyclic sulfonamides have also been included in the study. All types of activity have been detected, with several medium potency inhibitors (K(I)s in the range of 34-220 nM), whereas ethoxzolamide and several halogenated sulfanilamides showed stronger potency, with K(I)s in the range of 11-22 nM. The antiglaucoma sulfonamides used clinically, except dichlorophenamide, which is a moderate inhibitor (K(I) of 50 nM), as well as topiramate, indisulam, and sulpiride behave as very potent hCA XII inhibitors, with K(I)s in the range of 3.0-5.7 nM. Several subnanomolar inhibitors (K(I)s in the range of 0.30-0.85 nM) have also been detected. Compounds with excellent selectivity against hCA XII over hCA II have been found, showing selectivity ratios in the range of 177.7-566.7. Apparently, hCA XII is a target of the antiglaucoma sulfonamides, and potent hCA XII inhibitors may be developed/used for the management of hypoxic tumors, together with inhibitors of the other tumor-associated isozyme, CA IX.

Topics: Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Drug Design; Glaucoma; Humans; Isoenzymes; Structure-Activity Relationship; Sulfonamides

Reaction of polyamino-polycarboxylic acids or their dianhydrides with aromatic/heterocyclic sulfonamides possessing a free amino/imino/hydrazino/hydroxy group afforded mono- and bis-sulfonamides containing polyamino-polycarboxylic acid moieties in their molecule. The acids/anhydrides used in synthesis included IDA, NTA, EDDA, EDTA and EDTA dianhydride, DTPA and DTPA dianhydride, EGTA and EGTA dianhydride, and EDDHA, among others. All the newly prepared derivatives showed strong affinity toward isozymes I, II, and IV of carbonic anhydrase (CA). Metal complexes of the new compounds have also been prepared. Metal ions used in such preparations included di- and trivalent main-group and transition cations, such as Zn(II), Cu(II), Al(III), etc. Some of the new sulfonamides/disulfonamides obtained in this way, as well as their metal complexes, behaved as nanomolar CA inhibitors against isozymes II and IV, being slightly less effective in inhibiting isozyme I. Some of these sulfonamides as well as their metal complexes strongly lowered intraocular pressure (IOP) when applied topically, directly into the normotensive/glaucomatous rabbit eye, as 1-2% water solutions/suspensions. The good water solubility of these sulfonamide CA inhibitors, correlated with the neutral pH of their water solutions used in the ophthalmologic applications and the long duration of action of the IOP-lowering effect, makes them interesting candidates for developing novel types of antiglaucoma drugs devoid of serious topical side effects.

Topics: Animals; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Chelating Agents; Chloroform; Chromatography, High Pressure Liquid; Cornea; DNA, Complementary; Edetic Acid; Enzyme Inhibitors; Escherichia coli; Glaucoma; Humans; Hydrogen-Ion Concentration; Imino Acids; Kinetics; Male; Models, Chemical; Nitrilotriacetic Acid; Pentetic Acid; Pressure; Rabbits; Sulfonamides; Temperature; Time Factors; Ultraviolet Rays; Water

Reaction of diethylenetriamino pentaacetic acid (dtpa) dianhydride with aromatic/heterocyclic sulfonamides possessing a free amino/imino/hydrazino/hydroxy group afforded bis-sulfonamides containing metal-complexing, polyamino-polycarboxylic acid moieties in their molecule. The corresponding mono-sulfonamide derivatives of dtpa were also obtained by an alternative method, from the free acid. Zn(II) complexes of these new sulfonamides were then prepared. Many of these derivatives showed nanomolar affinity towards isozymes I, II and IV of carbonic anhydrase (CA). Some of the best inhibitors were applied as 2% water solutions/suspensions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed.

Topics: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors; Glaucoma; Intraocular Pressure; Pentetic Acid; Quantitative Structure-Activity Relationship; Rabbits; Sulfonamides; Zinc

Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino, or hydroxyl groups with Boc-Gly, Boc-Sar, TrS-Crt, or Boc-Gly-Gly (Sar = sarcosine, N-Me-Gly; Crt = creatine, N-amidinosarcosine; TrS = tritylsulfenyl; Boc = tert-butoxycarbonyl) in the presence of carbodiimide derivatives afforded after removal of the protecting groups a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic, or trifluoromethanesulfonic). 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. Efficient inhibition was observed against all three isozymes and especially against CA II and 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 synthesized were applied as 2% water solutions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. Thus, the aminoacyl/dipeptidyl tail conferring water solubility to these sulfonamide CA inhibitors coupled with strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity.

Topics: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cell Membrane Permeability; Cornea; Delayed-Action Preparations; Dipeptides; Disease Models, Animal; Glaucoma; Humans; Intraocular Pressure; Isoenzymes; Models, Molecular; Rabbits; Solubility; Sulfonamides; Time Factors

Ethoxzolamide and several derivatives (1-6) were synthesized and evaluated for carbonic anhydrase inhibition (CAI), solubility, pKa, distribution, and corneal permeability. The 6-hydroxy (5) and, particularly, the 6-chloro (6) analogues have the best combination of properties for penetrating the site of action and reducing intraocular pressure. Both 5 and 6 exhibited topical effectiveness in the normal rabbit, with 6 showing greater potency.

Topics: Animals; Carbonic Anhydrase Inhibitors; Ethoxzolamide; Glaucoma; Rabbits; Thiazoles