Inhibitor of carbonic anhydrase

Figure 12. Oligoglycine-linked para-substituted benzenesulfonamides as inhibitors of carbonic anhydrase II.

Aromatic sulfonamides are specific inhibitors of carbonic anhydrase (E). The apparent second-order rate constants for association of p-nitrobenzenesulfonamide with (a) carbonic anhydrase-B and (b) the carboxymethylated derivative of the enzyme are shown against pH in Figure 1.14. Estimate using equations (1.225) and (1.226) the values for pAig, and k and he two possible schemes shown for both carbonic... 

Mechanism of Action A noncompetitive inhibitor of carbonic anhydrase that inhibits the enzyme at the luminal border of cells of the proximal tubule. Increases urine volume and changes to an alkaline pH with subsequent decreases in the excretion of ti-tratable acid and ammonia Therapeutic Effect Produces a diuretic and antiglaucoma effect. 

A series of 5-substituted thieno[2,3-. ]thiophene-2-sulfonamides 159-162 and 6,6-dioxidothieno[2,3- ]thiophene-2-sulfonamides 163-166 were prepared for evaluation as inhibitors of carbonic anhydrase II. Oxidation of 5-substituted thieno[2,3-. ]thiophene-2-sulfonamides provided the first examples of 6,6-dioxidothieno[2,3-3]thiophene-2-sulfona-mides. It was found that compounds with the more acidic SO2NH2 group showed higher activity for human carbonic... 

Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic anhydrase. Renal excretion of solubilizing factors (eg, citrate) may also decline with chronic use. Calcium salts are relatively insoluble at alkaline pH, which means that the potential for renal stone formation from these salts is enhanced. 

A third problem with the mitochondrial theory of biomineralization is that many mineralized tissues contain carbonate rather than phosphate. Since bicarbonate ions do not pass across mitochondrial membranes with any ease, it has now been shown that in phosphate-free buffers, calcium will enter mitochondria if dissolved carbon dioxide is available. It appears that some mitochondria possess carbonic an-hydrase activity on the inner membrane or in the mitochondrial matrix and are thus able to synthesize bicarbonate within the organelle. In such cases, inhibitors of carbonic anhydrase block the accumulation of calcium and carbonate ions622) since crystals of calcite have been identified in the mitochondria of earthworms calci-ferous glands623. These cells freqently showed spherical granules in the cytoplasm and lumen of the glands during phases of mineral secretion and it was suggested that they were aspects of cellular breakdown which occurred at these times. 

A great advance in potency was achieved with the 1,2,4-benzothiadiazine 1,1-dioxide chlorothiazide (190), a cyclized aniline-2,4-disulfonamide which is a weaker inhibitor of carbonic anhydrase than acetazolamide, but a more powerful diuretic. The major contribution to diuretic activity in these compounds must come from some factor other than the inhibition of carbonic anhydrase since a ten-fold increase in activity was seen in the reduced compound hydrochlorothiazide (191 R1 = R2 = H, R3 = CI) which has only one-tenth of... 

The most powerful and specific inhibitors of carbonic anhydrase are certain aromatic or heterocyclic sulfonamides containing an unsubstituted R—SO2NH2 group (28). Inhibitors of this type are of great value in biochemical and physiological studies of carbonic anhydrase action and have found some therapeutic applications (28). As the various factors involved in their interaction with the enzyme have been extensively discussed at a recent symposium (51, 52) they will only be briefly mentioned here. 

Fig. 19. Sulfonamide-substituted Gd-DTPA complex that can act as an inhibitor of carbonic anhydrase...

Answer The graph gives us several pieces of information. First, the inhibitor prevents the enzyme from achieving the same Fmax as in the absence of inhibitor. Second, the overall shape of the two curves is very similar at any [S] the ratio of the two velocities ( inhibitor) is the same. Third, the velocity does not change very much above [S] = 1 mM, so at much higher [S] the observed velocity is essentially Vmax for each curve. Fourth, if we estimate the [S] at which -2-Fmax is achieved, this value is nearly identical for both curves. Noncompetitive inhibition, a special form of mixed inhibition that is rarely observed, alters the Fmax of enzymes but leaves Km unchanged. Thus, acetazolamide acts as a noncompetitive (mixed) inhibitor of carbonic anhydrase. 

The crystal structure of acetazolamide (5-acetamido-l,3,4-thiadiazole-2-sulfonamide), a potent inhibitor of carbonic anhydrase, is known. Bond distances are shown in (17) <74JCS(P2)532). 

For topical therapy of open-angle glaucoma, the following groups of drugs can be used for reducing production of aqueous humor, p-blockers (e. g., timolol), a2-agonists (clonidine, brimonidine), and inhibitors of carbonic anhydrase (dorzolamide, brinzola-mide). 

Figure 10 Inhibitors of carbonic anhydrase II. Compounds 9 and 10 are subnanomolar inhibitors identified through virtual screening. Compound 8 is the marketed drug dorzolamide.

Dichlorphenamide is similar, but a more potent inhibitor of carbonic anhydrase. 

Several Cr111 complexes with activated amido donor ligands (e.g., amides of carboxylic or sulfonic acids) have been described, but none of them have been crystallographically characterized.132,479 Complexes of Cr111 with 2-sulfonamide-1,3,4-thiadiazol derivatives act as potent inhibitors of carbonic anhydrases and may have potential use as anti-inflammatory or antidiabetic drugs.479,480... 

Mann, T., Keilin, D. Sulphanilamide as a specific inhibitor of carbonic anhydrase. Nature 1940, 146, 164-165. 

CAIs reduce lOP by decreasing ciliary body aqueous humor secretion. CAIs appear to inhibit aqueous production by blocking active secretion of sodium and bicarbonate ions from the ciliary body to the aqueous humor. Topical CAIs such as dorzolamide and brin-zolamide are well tolerated and are indicated for monotherapy or adjunctive therapy of open-angle glaucoma and ocular hypertension. Relatively specific inhibitors of carbonic anhydrase enzyme II such as dorzolamide and brinzolamide reduce lOP by 15% to 26%. 

Tetrazole- C and 1,2,4-triazole-1,2- N2 were found to be good inhibitors of carbonic anhydrase . ... 

The fluorinated aromatic sulfonamides (31) bind tightly to carbonic anhydrase (CA) II enzyme and show their inhibitory activity. The activities for fluorinated inhibitors of carbonic anhydrase increase in the order of non-F, 2-F, 2,5-F2, 3,4,5-F3, 2,3,5,6-F4, and 2,3,4,5,6-Fs in 31 (1.8, 0.73, 0.55, 0.55, 0.53, 0.44 nM, respectively). The increased activity is due to their hydrophobicity and specific contacts between the fluoroaromatic ring and the Phe131 site of the protein [11]. The octanol/water partition coefficients (log P) measure the hydrophobicity of each compound and increase with the level of fluorine substitution. 

The search was rewarding and opened up new vistas. The first breakthrough in this field was acetazolamide, a potent inhibitor of carbonic anhydrase. This compound induces increased sodium ion excretion and diuresis. It found wide medicinal application in the treatment of cardiac edema, acting presumably by suppression of carbonic anhydrase activity in the renal tubules. Unfortunately, drug tolerance developed in patients, limiting its utility. This deficiency stimulated medicinal chemists to persist in the modification of the sulfanilamide molecule and led to the discovery of chlorothiazide and the thiazide family of drugs. 

When sulfanilamide was introdnced as a chemotherapeutic agent, metabolic acidosis was recognized as a side effect. This observation led to the demonstration that snl-fanilamide is an inhibitor of carbonic anhydrase. Snbse-quently, an enormous number of sulfonamides were synthesized and tested for the ability to inhibit carbonic anhydrase of these componnds, acetazolamide has been studied most extensively. Three carbonic anhydrase inhibitors currently are available in the United States—acetazolamide, dichlorphenamide (Daranide), and methazolamide (GlaucTabs). The common molecnlar motif of available carbonic anhydrase inhibitors is an nnsnbstitnted sulfonamide moiety. 

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