Ординатура / Офтальмология / Английские материалы / Carbonic Anhydrase Its Inhibitors and Activators_Supuran, Scozzafava, Conway_2004

hydrochloric acid. The liberated compounds would then inhibit the enzymes involved in gastric acid production: the sulfonamides would bind within the CA active site, whereas the sulfenyl chlorides would inactivate (in an omeprazole-like manner) the gastric H+/K+-ATPase by alkylating the critical cysteine residues of this enzyme (Supuran et al. 1997a; Scozzafava and Supuran 1998b).

Klebe’s group detected several potent hCA II inhibitors by computer-aided drug design (Gruneberg et al. 2001). Three of these compounds, 4.258 to 4.260 showed nanomolar affinity to hCA II, and the x-ray structure has also been resolved for two of them. Kehayova et al. (1999) reported a hydrophobic CAI of type 4.261 that possessed a photolabile group derived from o-nitrophenylglycine. It is stated that such compounds might be useful for the site-specific delivery of prodrugs, for instance to the eye, but the high-energy UV radiation needed to liberate the active inhibitor (p-H2NO2S-C6H4CONHCH2C6F5) would probably do more harm than good to the eye tissues.

Reaction of tert-butyl-dimethylsilyl (TBDMS)-protected bile acids (cholic, chenodeoxycholic, deoxycholic, lithocholic, ursodeoxycholic acids) or dehydrocholic acid with aromatic/heterocyclic sulfonamides possessing free amino/hydroxy moieties, of types A–T, in the presence of carbodiimides afforded after deprotection of the OTBDMS ethers a series of sulfonamides incorporating bile acid moieties in their molecules (Scozzafava and Supuran 2002). Many such derivatives, of which 4.262 are illustrative representatives, showed strong inhibitory properties against three isozymes CA I, CA II and CA IV. Some of the most active derivatives,

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4.262 (R7, R12 = H, OH, O-TBDMSi)

incorporating 1,3,4-thiadiazole-2-sulfonamide or benzothiazole-2-sulfonamide functionalities in their molecules, showed low nanomolar affinity for CA II and CA IV. Furthermore, the bioavailability of these derivatives in rabbits was comparable to that of acetazolamide, being ca. 85 to 90%, making them promising candidates for systemically acting CA inhibitors (Scozzafava and Supuran 2002).

Unsaturated primary sulfonamides have only recently been investigated for their interaction with CA (Chazalette et al. 2001). Such compounds, and more precisely allyl-sulfonamide 4.263 and trans-styrene sulfonamide 4.264, behave as nanomolar inhibitors of the physiologically relevant isozymes CA I and CA II (Chazalette et al. 2001).

4.9 ALIPHATIC SULFONAMIDES

Aliphatic sulfonamides of the type R-SO2NH2 (R = Me, PhCH2) were investigated as CAIs by Maren (1967), who showed that in contrast to aromatic/heterocyclic sulfonamides, such compounds are extremely weak inhibitors (IC50 > 10–4 M). This lack of activity was correlated with the absence of the cyclic moiety that would influence the stability of the enzyme–inhibitor (EI) complexes in two ways: (1) by an acidifying effect on the SO2NH2 protons (because of the electron-attracting properties of the aryl/hetaryl moieties), and (2) by the cyclic moiety in the molecule of CAIs participating in hydrophobic and van der Waals interactions, as well as hydrogen bond networks with amino acid side chains within the active site.

In reality, the situation was much more complex, and the simple assertions made were shown to be basically incorrect by the report of Maren and Conroy (1993) that

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TABLE 4.22

Dog CA II Inhibition with

Aliphatic Sulfonamides 4.265

RSO2NH2

4.265

Source: From Maren T.H., and Conroy, C.W. (1993) Journal of Biological Chemistry 268, 26233–26239. With permission.

some types of aliphatic sulfonamides can act as very strong CAIs. In Table 4.22, data are presented for some halogeno/polyhalogeno-alkylsulfonamides (4.265b–i), as compared to the simplest such sulfonamide methanesulfonamide 4.265a. The data show that an increasing number of halogen atoms in position 1 or 2, or both, from the SO2NH2 group has the effect of strengthening the acidity of the SO2NH2 protons and a concomitant dramatic increase in CA inhibitory properties. In practice, trichloromethyl and pentafluoroethyl derivatives 4.265f, h are as strong CAIs as acetazolamide, whereas the perfluoroderivatives 4.265g, i are even more potent against dog CA II (Maren and Conroy 1993).

Even more interesting inhibitors of this class, of types 4.266 to 4.270, have been reported by Scholz et al. (1993) in their search for antiglaucoma agents with a topical action. Commencing from the modestly active lead 4.266 (a micromolar inhibitor), it has been observed that (1) the aromatic ring was not necessary for inducing good CA inhibitory properties in this type of compounds; (2) lengthening the alkyl chain connected to the sulfamoylmethyl-sulfoxide moiety of the molecule was highly beneficial for achieving very good affinity for the enzyme (the study conducted on hCA II; Scholz et al. 1993). Indeed, the phenethyl 4.267 and especially n-octyl 4.268 derivatives show an increased affinity for CA II as compared to the lead 4.266. Because the purely aliphatic compound 4.268 was the best inhibitor (IC50 22 nM), the hydrogen atoms in position α to the sulfamoyl moiety were substituted by one or two halogens (fluorine and chlorine) or by methyl groups. Only the monohalogeno derivatives 4.269 and 4.270 possessed good CA inhibitory activities; the dihalogenosubstituted or the methyl derivatives were only micromolar inhibitors.

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4.10 FUTURE PROSPECTS OF CAIs

CAIs are widely used as therapeutic agents to manage or prevent many diseases. This is mainly because of the wide distribution of the 14 vertebrate CAs in many cells, tissues and organs, wherein they play crucial physiological functions. The available pharmacological agents are still far from perfect. They possess many undesired side effects, mainly because they lack selectivity for the different CA isozymes. Thus, developing isozyme-specific or at least organ-selective sulfonamide inhibitors will be highly beneficial both for obtaining novel types of drugs, devoid of major side effects, as well as for many physiological studies in which specific/selective inhibitors will be valuable tools for understanding the physiology of these enzymes. Prospects for achieving such a goal are not very optimistic at present, because of the high similarity between several isozymes in their interaction with sulfonamide inhibitors. Some progress in this field has been recently recorded, as shown in this chapter, by developing low-molecular-weight membrane-impermeant inhibitors, which being excluded from the intracellular space inhibit selectively only membrane-associated and not cytosolic CA isozymes.

Important advances have been made in the past few years in developing topically effective CAIs for treating glaucoma, with two drugs being available: dorzolamide and brinzolamide. These drugs have reduced many of the undesired side effects observed with the systemically used CAIs for treating glaucoma. Both dorzolamide and brinzolamide are effective antiglaucoma agents, but because of local side effects they tend to pose tolerability problems in many patients. This is probably because these two compounds are salts of weak bases with a very strong acid, and thus the pH of the administered drug is relatively acidic. Thus, the search for novel types of topically acting antiglaucoma sulfonamides continues. Recently, an approach different (and more general) from the ring approach, which led to the drugs mentioned previously, has been reported for preparing topical antiglaucoma CAIs. This consists of introducing water-solubilizing tails to the molecules of aromatic/heterocyclic

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sulfonamides. Several of the compounds obtained this way, which can form salts with pH values in both the slightly acidic and the slightly basic region (pH 6.5 to 7.5), showed very potent IOP-lowering properties in several animal models of glaucoma, and some of them are under clinical evaluation. Furthermore, such agents showed a longer IOP-lowering effect than the first-generation topically acting sulfonamides did, which might be a valuable feature in a new drug from this family of pharmacological agents. In our view, another important aspect for the future applications of CAIs in ophthalmology regards their possible use in treating macular edema and related degenerative pathologies, for which no effective treatment is known at present. (See Chapter 8 of this book.)

The potential of CAIs to treat epilepsy and other neurological/neuromuscular disorders is far from having been fully exploited. Thus, no specific brain enzyme CAI has been reported yet, but a specific cerebrovasodilator from this class of pharmacological agents will be a valuable drug and also an interesting diagnostic tool, because acetazolamide is widely employed (the so-called acetazolamide-test) for assessing cerebrovascular reactivity in normal and pathological states (Supuran and Scozzafava 2000a). Even so, the “imperfect” drug acetazolamide represents the only available therapy of choice in many minor neurological disorders, such as familial hemiplegic migraine and ataxia, tardive dyskinesia and hypoand hyperkalemic periodic paralysis (Supuran and Scozzafava 2000a). The development of more selective CAIs of this type will be an interesting challenge for medicinal chemists and pharmacologists.

Sulfonamide CAIs played a crucial role in the understanding of renal physiology and pharmacology and led to the development of widely used diuretic drugs, such as the benzothiadiazine and high-ceiling diuretics. Still, few advances have been ultimately recorded in this field, probably because a large number of clinically approved diuretics are available. An orphan drug of this class, benzolamide, still awaits a wider use. Few studies are also available on the therapeutic potential of CAIs in osteoporosis. The development of bone-targeted sulfonamides will lead to drugs devoid of severe systemic effects, but little progress has been registered in this field (Supuran and Scozzafava 2000a).

A recent and new field in CAI research has been opened by the report of the potent antitumor properties of an entire class of sulfonamide CAIs, as well as by the isolation of some CA isozymes predominantly present in tumor cells. The mechanisms by which sulfonamides inhibit tumor cell growth are only beginning to be understood, and we predict important advances in this direction because several laboratories are involved in the synthesis, evaluation and in vitro/in vivo antitumor testing of novel classes of sulfonamides with potential applications as anticancer therapeutic agents. Indeed, a compound of this type, indisulam, has progressed to Phase II clinical trials for use in treating solid tumors.

No pharmacological agents from this class of compounds have so far been developed for inhibiting the liver enzyme (predominantly CA V), and because this is involved in biosynthetic reactions (urea synthesis, glucogenesis, etc.), such agents might be useful in some metabolic dysfunctions. In fact, CA V remains one of the least studied major CA isozymes, and even its catalytic mechanism is not fully understood.

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Very few studies are available on the inhibition of nonvertebrate CAs. Because CAs were recently shown to be present in a multitude of parasites (e.g., Plasmodium spp.), bacteria and archaea, it is possible to develop CAI-based antibiotics or antimalarial therapies.

CAs and their inhibitors are indeed remarkable — after many years of intense research in this field, they continue to offer interesting opportunities for developing novel drugs and new diagnostic tools and for understanding in greater depth the fundamental processes of the life sciences.

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