Sulfonamides, carbonic anhydrase inhibitors

Menziani, M.C. and De Benedetti, P. (1991) Direct and indirect theoretical QSAR modelling in sulfonamide carbonic anhydrase inhibitors, in QSAR Rational Approaches on the Design of Bioactive Compounds (eds C. Silipoand A. Vittoria), Elsevier, Amsterdam, pp. 331. 

The development of sulfonamide carbonic anhydrase inhibitors was based on the observation that antibacterial sulfanilamides produce alkaline urine. This discovery led to the development of acetazolamide (8.29), a thiadiazole derivative. It is not an ideal drug because it promotes K+ excretion and causes a very high urine pH. Since chloride ions are not excreted simultaneously, systemic acidosis also results. Much more useful are the chlorothiazide (8.30) derivatives, which are widely used as oral diuretic drugs. These compounds differ from one another mainly in the nature of the substituent on C3 ... 

Maestrclli, E, Mura, R, Casini, A., Mincione, F., Scozzafava, A., and Supuran.C.T. (2002), Cyclodextrin complexes of sulfonamide carbonic anhydrase inhibitors as long-lasting topically acting antiglaucoma agents,/. Pharm. Sci., 91(10), 2211-2219. 

Numerous substances such as calcium, magnesium, and phosphate, administered to rats and/or mice, have been demonstrated to lead to formation of urinary solids and are listed in Table 19.1. This table includes not only a large number of natural, essential ingredients in om diet, but also a number of substances that are formed from normal intermediary metabolism, such as carbonate, oxalate, cystine, urate, and uracil, which are present in normal urine. Numerous synthetic chemicals also produce urinary solids when administered at very high doses, including agrichemicals (such as sulfosulfuron and Fosetyl-Al), industrial chemicals (such as melamine), and pharmaceuticals (such as sulfonamides, carbonic anhydrase inhibitors, and HIV protease inhibitors). 

Edelhauser HF, Maren TH. Permeability of human cornea and sclera to sulfonamide carbonic anhydrase inhibitors. Arch Ophthalmol 1988 106 1110-1115. 

The sulfonamide carbonic anhydrase inhibitors, such as sulfanilamide, acet-azolamide, and their congeners, have contributed significantly to the knowledge of renal function—e.g., the site and origin of the hydrogen ion excretion and the site of potassium ion excretion. 

De Benedetti PG, Menziani MC, Cocchi M, Frassineti C. A quantum chemical QSAR analysis of carbonic anhydrase inhibition by heterocyclic sulfonamides. Sulfonamide carbonic anhydrase inhibitors Quantum chemical QSAR. Quant Struct-Act Relat 1987 6 51-53. 

Jones and co-workers used regression analyses to study the effects of field constants and resonance parameters (110) of some carbamate derivatives on their penetration and detoxication with some success (111). Similar studies have also been made by Fukuto and co-workers using selected oximes and their anticholinesterase activities (112). Kakeya et al. used chemical shifts and valence force constants in addition to other thermodynamic parameters in the structure-activity study of a series of sulfonamide carbonic anhydrase inhibitors (113). 

A hydrogen-bonding mechanism that acts competitively explains the action of certain sulfonamide carbonic anhydrase inhibitors that have diuretic and antiglaucoma properties. Carbonic acid is thought to be the normal substrate that fits into a cavity of and complexes... 

Using a variety of physicochemical parameters, Kakeya et al. have performed a structure-activity study on a series of sulfonamide carbonic anhydrase inhibitors. Hammett s o constants were found to vary linearly with pKa, chemical shift of the sulfamoyl protons, and the valence-force constant, fj., of the S=0 bond. It was found that compounds with a large a value, a large f- for the S=0 bond, and a large chemical shift for the sulfamoyl group showed a strong inhibitory activity for carbonic anhydrase this illustrates the importance of electronic effects in the activity of sulfonamide derivatives. ... 

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

Viader MP, McKeever BM, Navia MA. Thienothiopyran-2-sulfonamides novel topically active carbonic anhydrase inhibitors for the treatment of glaucoma. J Med Chem 1989 32 2510-13. 

Local side effects include burning, stinging, itching, foreign body sensation, dry eyes, and conjunctivitis. Brinzolamide may have a lower incidence of these side effects since the drug is in a neutral pH solution. Dorzolamide has been reported to cause irreversible corneal decompensation. Taste abnormalities have been reported with each agent. Both topical carbonic anhydrase inhibitors are sulfonamides and are contraindicated in patients with history of sulfonamide hypersensitivity.10,13... 

Not all drugs contain functional groups that lend themselves readily to prodrug derivatization. A case in point is the carbonic anhydrase inhibitors such as acetazolamide, ethoxzolamide, and methazolamide. Although the amino functional group of their sulfonamide moiety can be methylated, the resulting analogs... 

Acetazolamide is an aromatic sulfonamide used as a carbonic anhydrase inhibitor. It facilitates production of alkahne urine with an elevated biocarbonate, sodium, and potassium ion concentrations. By inhibiting carbonic anhydrase, the drug suppresses reabsorption of sodium ions in exchange for hydrogen ions, increases reflux of bicarbonate and sodium ions and reduces reflux of chloride ions. During this process, chloride ions are kept in the kidneys to cover of insufficiency of bicarbonate ions, and for keeping an ion balance. Electrolytic contents of fluid secreted by the kidneys in patients taking carbonic anhydrase inhibitors are characterized by elevated levels of sodium, potassium, and bicarbonate ions and a moderate increase in water level. Urine becomes basic, and the concentration of bicarbonate in the plasma is reduced. 

Hypersensitivity to sulfonamides or chemically related drugs (eg, sulfonylureas, thiazide and loop diuretics, carbonic anhydrase inhibitors, sunscreens with PABA, local anesthetics) pregnancy at term lactation infants less than 2 months of age (except in congenital toxoplasmosis as adjunct with pyrimethamine) porphyria salicylate hypersensitivity. 

Sulfasalazine is contraindicated in individuals with hypersensitivity to salicylates, sulfonamides, sulfonylureas, and certain diuretics (furosemide, thiazides, and carbonic anhydrase inhibitors). Because it can cause kernicterus, sulfasalazine is contraindicated in infants and children under 2 years of age. Sulfasalazine passes into breast milk and is therefore contraindicated for nursing mothers. Similarly, pregnant women near term should not use this drug, although it appears to be the safest of the DMARDs during early pregnancy. 

Orally administered carbonic anhydrase inhibitors lower the intraocular pressure of glaucoma patients, however they induce a number of intolerable side effects associated with extraocular inhibition of the enzyme [5,6]. Thus, much research has been directed towards the search for a topically effective agent. Several compounds have been synthesized since the 1980 s in Merck Sharp Dohme Research Laboratories, and have been found to be topically active in man [7]. Unfortunately, many of these compounds were not very soluble. Attempts to obtain an active carbonic anhydrase inhibitor with good solubility resulted in the synthesis of Dorzolamide hydrochloride [8,9], which was first made available for pharmacological evaluation in 1987. Like other carbonic anhydrase inhibitors sulfonamides (such as acetazolamide, ethoxzolaniide, and methazolamide) dorzolamide is an inhibitor of human carbonic anhydrase isoenzymes I, II, and IV. In contrast to the other sulfonamides, dorzolamide is a potent inhibitor of isoenzymes II and IV, and a weak inhibitor of isoenzyme I [ 10]. Isoenzyme II is thought to play a major role in aqueous humor secretion. 

Chemical Class Carbonic anhydrase inhibitor sulfonamide derivative... 

Carbonic anhydrase inhibitors were the forerunners of modern diuretics. They were discovered when it was found that bacteriostatic sulfonamides caused an alkaline diuresis and hyperchloremic metabolic acidosis. With the development of newer agents, carbonic anhydrase inhibitors are now rarely used as diuretics, but they still have several specific applications that are discussed below. The prototypical carbonic anhydrase inhibitor is acetazolamide. 

Like carbonic anhydrase inhibitors and many loop diuretics, all of the thiazides have an unsubstituted sulfonamide group (Figure 15-... 

Thiadiazole-2-sulfonamide, 5-acetamido-carbonic anhydrase inhibitor, 6, 576 crystal structure, 6, 548... 

Taylor, P. W., and Burgen, A. S. V. Kinetics of carbonic anhydrase inhibitor complex formation. A comparison of anion- and sulfonamide-binding mechanisms. Biochemistry JO, 3859-3866(1971). 

The two prototypical drugs of this group are furosemide and ethacrynic acid. The structures of several loop diuretics are shown in Figure 15-7. Like the carbonic anhydrase inhibitors, furosemide, bumetanide, and torsemide are sulfonamide derivatives. 

All sulfonamides and their derivatives, including carbonic anhydrase inhibitors, thiazides, furosemide, bumetanide, torsemide, diazoxide, and the sulfonylurea hypoglycemic agents, are cross-allergenic. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract (see below). Stevens-Johnson syndrome, although relatively uncommon (ie, less than 1% of treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see Urinary Tract Disturbances), hepatitis, and, rarely, polyarteritis nodosa and psychosis. 

The thieno[2,3-Z ]furan-2-sulfonamides (346) (Scheme 28) have been prepared and evaluated as topical carbonic anhydrase inhibitors <91JMC1805>. 

The thieno[2,3-6]furan-2-sulfonamides (11), thieno[2,3-6]thiophene-2-sulfonamides, and thieno-[3,2-6]thiophene-2-sulfonamides were prepared and found to be a new class of topically active ocular hypotensive carbonic anhydrase inhibitors (91JMC1805,92JMC3027). 

Acetazolamide [a set a ZOLE a mide] is a sulfonamide without antibacterial activity. Its main action is to inhibit the enzyme carbonic anhydrase in the proximal tubular epithelial cells. However, carbonic anhydrase inhibitors are more often used for their other pharmacologic actions rather than for their diuretic effect, because these agents are much less efficacious than the thiazides or loop diuretics. 

The thiazides are the most widely used of the diuretic drugs. They are sulfonamide derivatives and are related in structure to the carbonic anhydrase inhibitors. The thiazides have significantly greater diuretic activity than acetazolamide, and they act on the kidney by different mechanisms. All thiazides affect the distal tubule, and all have equal maximum diuretic effect, differing only in potency, expressed on a per -milligram basis. 

Lin JH, Ulm EH, Los LE (1991) Dose-dependent stereopharmacokinetics of 5,6-dihydro-4H-4 (isobutylamino)-thieno(2,3-B)thiopyran-2-sulfonamide-7,7-dioxide, a potent carbonic anhydrase inhibitor, in rats. Drug Metabolism Disposition 19 233... 

Figure 2.5 In addition to its antibacterial activity, sulfanilamide 11 (Figure 2.4) inhibits the enzyme carbonic anhydrase. Acetazolamide 12 is much more potent as a carbonic anhydrase inhibitor but its clinical use as diuretic was impaired by some serious side effects. Hydrochlorothiazide 13 is the prototype of orally active saluretic sulfonamide diuretics. Furosemide (frusemide) 14 and bumetanide 15 are so-called loop diuretics .

---