Biomedical subjects

Angela Casini

Publications and source records attributed to Angela Casini.

At least 37 records · Page 2Linked to original sources

PubMed2004

Carbonic anhydrase inhibitors: the first selective, membrane-impermeant inhibitors targeting the tumor-associated isozyme IX.

The inhibition of the tumor-associated transmembrane carbonic anhydrase IX (CA IX) isozyme possessing an extracellular active site has been investigated with a series of positively-charged, pyridinium derivatives of sulfanilamide, homosulfanilamide and 4-aminoethylbenzenesulfonamide. Inhibition data for the physiologically relevant isozymes I and II (cytosolic forms) and IV (membrane-bound) were also provided for comparison. A very interesting inhibition profile against CA IX with these sulfonamides has been observed. Several nanomolar (K(i)'s in the range of 6-54 nM) CA IX inhibitors have also been detected. Because CA IX is a highly active isozyme predominantly expressed in tumor tissues with bad prognosis of disease progression, this finding is very promising for the potential design of CA IX-specific inhibitors with applications as anti-tumor agents. This is the first report of inhibitors that may selectively target CA IX, due to their membrane-impermeability and high affinity for this clinically relevant isozyme.

Antigens, Neoplasm↗

PubMed2004

Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition.

By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.

Animals↗

PubMed2004

Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with the antipsychotic drug sulpiride.

The X-ray crystal structure for the adduct of human carbonic anhydrase (hCA) II with sulpiride, a sulfonamide derivative clinically used as antipsychotic drug, has been resolved at a resolution of 1.6 A. This compound is an effective inhibitor of the physiologically most relevant isozyme hCA II (K(i) of 40 nM), being only a moderate or moderate-weak inhibitor of the cytosolic isozyme hCA I (K(i) of 1200 nM) and the membrane-bound isozyme hCA IV (K(i) of 620 nM). Sulpiride shows CA inhibitory properties of the same magnitude as dichlorophenamide, a clinically used antiglaucoma sulfonamide, or valdecoxib, a COX-2 selective inhibitor recently shown to inhibit CA. The binding of sulpiride to the hCA II active site is similar to that of other sulfonamide inhibitors, considering the interactions of the sulfonamide zinc anchoring group, but differs considerably when the organic scaffold of the molecule is analyzed. Indeed, one unprecedented hydrogen bond involving the imino moiety of the carboxamido group of sulpiride and a water molecule was observed, together with a unique stacking interaction of the N-methyl-pyrrolidine ring of the inhibitor and the aromatic ring of Phe 131 of the enzyme active site, which has been observed only recently in another CA-sulfonamide complex.

Antipsychotic Agents↗

PubMed2004

Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX.

E7070 [N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] is an anticancer drug candidate under clinical development for the treatment of several types of cancers. We prove here that this compound also acts as a potent carbonic anhydrase (CA) inhibitor. Similarly to the clinically used drugs acetazolamide, methazolamide and topiramate, E7070 showed inhibition constants in the range of 15-31nM against isozymes I, II and IX, being slightly less effective as a CA IV inhibitor (K(i) of 65nM). The X-ray crystal structure of the adduct of hCA II with E7070 revealed unprecedented interactions between the inhibitor and the active site, with three different conformations of the chloroindole fragment of the inhibitor interacting with different amino acid residues/water molecules of the enzyme. A superimposition of these conformations with those of other sulfonamide/sulfamate CA inhibitors indicated that similar regions of the hCA II active site could be involved in the interaction with inhibitors.

Animals↗

PubMed2004

Carbonic anhydrase inhibitors: N-(p-sulfamoylphenyl)-alpha-D-glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits.

A series of N-(p-sulfamoylphenyl)-alpha-D-glycopyranosylamines was prepared by reaction of sulfanilamide with different monosaccharides in the presence of ammonium chloride. The new compounds were investigated for inhibition of the metallo-enzyme carbonic anhydrase (CA, EC 4.2.1.1), involved in aqueous humor secretion within the mammalian eye. Isozymes CA I and CA II were strongly inhibited by some of these compounds, which showed inhibition constants in the range of 510-1200 nM against CA I and 10-25 nM against CA II, similarly to clinically used sulfonamides, such as acetazolamide, methazolamide, dichlorophenamide, dorzolamide and brinzolamide. The presence of sugar moieties in these molecules induced an enhanced water solubility as compared to other sulfonamides. In hypertensive rabbits (a widely used animal model of glaucoma), two of the new compounds showed strong and long-lasting intraocular pressure (IOP) lowering, being more effective than dorzolamide and brinzolamide, the two clinically used, topically acting antiglaucoma sulfonamides with CA inhibitory properties.

Administration, Topical↗

PubMed2004

Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with EMATE, a dual inhibitor of carbonic anhydrases and steroid sulfatase.

The X-ray crystal structure for the adduct of human carbonic anhydrase II (hCA II) with estrone-3-O-sulfamate (EMATE), an antiendocrine agent showing both CA and estrone sulfatase inhibitory properties, has been resolved at a resolution of 1.5A. Its binding to the enzyme is similar to that of other sulfamates/sulfonamides, considering the interactions of the zinc anchoring group, but differs considerably when the steroidal scaffold of the inhibitor is analyzed. This part of the inhibitor interacts only within the hydrophobic half of the CA active site, interacting with residues Val 121, Phe 131, Val 135 and Pro 202, and leaving the hydrophilic half able to accommodate several water molecules not present in the uncomplexed enzyme. In addition, a very short bond of 1.78A between the zinc ion and the coordinated nitrogen atom of the sulfamate moiety is observed, which may explain the high affinity of this inhibitor for hCA II (K(i) of 10nM).

Carbonic Anhydrase II↗

PubMed2004

Carbonic anhydrase inhibitors: aliphatic N-phosphorylated sulfamates--a novel zinc-anchoring group leading to nanomolar inhibitors.

A small library of phosphorylated sulfamates (N-(O-alkylsulfamoyl)-phosphoramidic acids) incorporating long aliphatic chains (C8-C16) has been synthesized and investigated for their interaction with two physiologically relevant carbonic anhydrase (CA) isozymes. These compounds behaved as very potent inhibitors of both isozymes, with inhibition constants in the range of 8.2-16.1nM against isozyme hCA I, and 5.3-11.9nM against isozyme hCA II. Activity was optimal for the n-octyl derivative (similarly with that of the corresponding unsubstituted sulfamates) and gradually decreased for the longer chain derivatives. Some of these compounds are much more effective CA inhibitors as compared to the clinically used derivatives acetazolamide, sulfanilamide or topiramate, which are used as standards for the enzymatic determinations. The phosphorylated sulfamate moiety represents a novel zinc-binding group for the design of effective CA inhibitors.

Binding Sites↗

PubMed2004

New developments on thromboxane and prostacyclin modulators part I: thromboxane modulators.

The pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases can be related to arachidonic acid (AA) metabolites. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2)(PGH(2)), which results from the enzymatic degradation of AA by the cyclooxygenases. TXA(2) is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction. It is involved in a series of major pathophysiological states such as asthma, myocardial ischemia, pulmonary hypertension, and thromboembolic disorders. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by several pharmaceutical companies since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. Moreover, the recent literature reported the interest of thromboxane modulators, which combine another pharmacological activity such as, platelet activating factor antagonism, angiotensin II antagonism, or 5-lipoxygenase inhibition. In this review, we will propose a description of the recently described thromboxane modulators of major interest from both a pharmacological and a chemical point of view.

Arachidonic Acid↗

PubMed2004

COX-2 selective inhibitors, carbonic anhydrase inhibition and anticancer properties of sulfonamides belonging to this class of pharmacological agents.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycaemic, antithyroid, protease inhibitory and anticancer activity among others. A recently developed class of pharmacological agents incorporating primary sulfamoyl moieties in their molecule is constituted by the COX-2 selective inhibitors, with at least two clinically used drugs, celecoxib and valdecoxib. Another drug of this class, rofecoxib, does not contain sulfonamide moieties, but the isosteric and isoelectronic methylsulfone group. It was recently shown that the sulfonamide COX-2 selective inhibitors (but not the methylsulfone ones) also act as nanomolar inhibitors of several isozymes of the metallo-enzyme carbonic anhydrase (CA), some of which are strongly involved in tumourigenesis. In consequence, the potent anticancer effects of the sulfonamide COX-2 selective inhibitors and the much weaker such effects of rofecoxib, reported ultimately by many researchers, may be explained by the contribution of CA inhibition to such processes in addition to COX-2 inhibition.

Animals↗

PubMed2004

Designing of Novel Carbonic Anhydrase Inhibitors and Activators.

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide spread enzymes, present in mammals in at least 14 different isoforms: some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII), while others are membrane-bound (CA IV, CA IX, CA XII and CA XIV); CA V is mitochondrial, and CA VI is secreted in the saliva. Three acatalytic forms are also known (CARP VIII, CARP X and CARP XI). Several important physiological and physio-pathological functions are played by many CA isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped in the design of potent inhibitors, some of which possess important clinical applications. The use of such CA inhibitors (CAIs) as antiglaucoma drugs will be discussed in detail, together with the recent developments that led to isozyme-specific and organ-selective inhibitors. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CAIs were shown to inhibit the growth of several tumor cell lines in vitro and in vivo, constituting thus interesting leads for developing novel antitumor therapies. Future prospects for drug design applications for inhibitors of these ubiquitous enzymes will be dealt with. Although activation of CAs has been a controversial issue for some time, recent kinetic, spectroscopic and X-ray crystallographic experiments offered an explanation for this phenomenon, based on the catalytic mechanism. It has been demonstrated recently, that molecules that act as carbonic anhydrase activators (CAAs) bind at the entrance of the enzyme active site participating in facilitated proton transfer processes between the active site and the reaction medium. In addition to CA II - activator adducts, X-ray crystallographic studies have also been reported for ternary complexes of this isozyme with activators and anion (azide) inhibitors. Structure-activity correlations for diverse classes of activators will be discussed for the isozymes for which the phenomenon has been studied, i.e., CA I, II, III and IV. The possible physiologic relevance of CA activation will also be addressed, together with the recent pharmacological applications of blood CA isozymes activators, as potential memory enhancing drugs.

Journal Article↗

PubMed2004

Designing of novel carbonic anhydrase inhibitors and activators.

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide spread enzymes, present in mammals in at least 14 different isoforms: some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII), while others are membrane-bound (CA IV, CA IX, CA XII and CA XIV); CA V is mitochondrial, and CA VI is secreted in the saliva. Three acatalytic forms are also known (CARP VIII, CARP X and CARP XI). Several important physiological and physio-pathological functions are played by many CA isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped in the design of potent inhibitors, some of which possess important clinical applications. The use of such CA inhibitors (CAIs) as antiglaucoma drugs will be discussed in detail, together with the recent developments that led to isozyme-specific and organ-selective inhibitors. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CAIs were shown to inhibit the growth of several tumor cell lines in vitro and in vivo, constituting thus interesting leads for developing novel antitumor therapies. Future prospects for drug design applications for inhibitors of these ubiquitous enzymes will be dealt with. Although activation of CAs has been a controversial issue for some time, recent kinetic, spectroscopic and X-ray crystallographic experiments offered an explanation for this phenomenon, based on the catalytic mechanism. It has been demonstrated recently, that molecules that act as carbonic anhydrase activators (CAAs) bind at the entrance of the enzyme active site participating in facilitated proton transfer processes between the active site and the reaction medium. In addition to CA II--activator adducts, X-ray crystallographic studies have also been reported for ternary complexes of this isozyme with activators and anion (azide) inhibitors. Structure-activity correlations for diverse classes of activators will be discussed for the isozymes for which the phenomenon has been studied, i.e., CA I, II, III and IV. The possible physiologic relevance of CA activation will also be addressed, together with the recent pharmacological applications of blood CA isozymes activators, as potential memory enhancing drugs.

Animals↗

PubMed2003

Carbonic anhydrase inhibitors: inhibition of transmembrane, tumor-associated isozyme IX, and cytosolic isozymes I and II with aliphatic sulfamates.

A series of aliphatic sulfamates and related derivatives incorporating cyclic/polycyclic (steroidal) moieties in their molecules has been synthesized and assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA) and, more precisely, of the cytosolic isozymes CA I and II and the transmembrane, tumor-associated isozyme CA IX. The most potent CA I inhibitor was n-tetradecyl sulfamate and some (substituted)benzyl/phenethyl sulfamates (inhibition constants in the low micromolar range). Against CA II, low nanomolar inhibitors (0.7-3.4 nM) were n-decyl sulfamate and the (substituted)benzyl/phenethyl derivatives mentioned above. Effective CA II inhibition was also observed for the hydroxy/keto derivatives of dehydroepiandrosterone sulfamate. Efficient CA IX inhibitory properties, with inhibition constants in the range of 9-23 nM, were observed for the aliphatic sulfamates C(10)-C(16) (with the most potent inhibitor being the n-dodecyl derivative) and the (substituted)benzyl/phenethyl sulfamates. The inhibition profile of the three investigated isozymes with this type of compound was rather different, allowing us to hope that the preparation of CA IX-selective inhibitors is possible (selectivity ratios toward hCA IX versus hCA II in the range of 5-63 has been observed for some of these compounds, whereas for the clinically used sulfonamides this parameter is in the range of 0.23-0.51). These data are critical for the design of novel antitumor therapies, mainly for hypoxic tumors that overexpress CA IX, which are nonresponsive to radiation or chemotherapy.

Antigens, Neoplasm↗

PubMed2003

Characterization of CA XIII, a novel member of the carbonic anhydrase isozyme family.

The carbonic anhydrase (CA) gene family has been reported to consist of at least 11 enzymatically active members and a few inactive homologous proteins. Recent analyses of human and mouse databases provided evidence that human and mouse genomes contain genes for still another novel CA isozyme hereby named CA XIII. In the present study, we modeled the structure of human CA XIII. This model revealed a globular molecule with high structural similarity to cytosolic isozymes, CA I, II, and III. Recombinant mouse CA XIII showed catalytic activity similar to those of mitochondrial CA V and cytosolic CA I, with k(cat)/K(m) of 4.3 x 10(7) m(-1) s(-1), and k(cat) of 8.3 x 10(4) s(-1). It is very susceptible to inhibition by sulfonamide and anionic inhibitors, with inhibition constants of 17 nm for acetazolamide, a clinically used sulfonamide, and of 0.25 microm, for cyanate, respectively. Using panels of cDNAs we evaluated human and mouse CA13 gene expression in a number of different tissues. In human tissues, positive signals were identified in the thymus, small intestine, spleen, prostate, ovary, colon, and testis. In mouse, positive tissues included the spleen, lung, kidney, heart, brain, skeletal muscle, and testis. We also investigated the cellular and subcellular localization of CA XIII in human and mouse tissues using an antibody raised against a polypeptide of 14 amino acids common for both human and mouse orthologues. Immunohistochemical staining showed a unique and widespread distribution pattern for CA XIII compared with the other cytosolic CA isozymes. In conclusion, the predicted amino acid sequence, structural model, distribution, and activity data suggest that CA XIII represents a novel enzyme, which may play important physiological roles in several organs.

Amino Acid Sequence↗

PubMed2003

Carbonic anhydrase inhibitors: topically acting antiglaucoma sulfonamides incorporating esters and amides of 3- and 4-carboxybenzolamide.

Reaction of 3- and 4-carboxybenzenesulfonyl chloride with 5-amino-1,3,4-thiadiazole-2-sulfonamide/5-imino-4-methyl-delta(2)-1,3,4-thiadiazoline-2-sulfonamide afforded two series of benzolamide analogues to which the carboxyl moiety has been derivatized as esters or amides, in order to reduce their very polar character. The new derivatives showed low nanomolar affinity for three carbonic anhydrase (CA) isozymes, CA I, II and IV, and were effective as topical antiglaucoma agents in normotensive rabbits. Efficacy of several of the new sulfonamides reported was better than that of the standard drugs dorzolamide and brinzolamide, whereas their duration of action was prolonged as compared to that of the clinically used drugs.

Administration, Topical↗

PubMed2003

Carbonic anhydrase activators. The selective serotonin reuptake inhibitors fluoxetine, sertraline and citalopram are strong activators of isozymes I and II.

The selective serotonin reuptake inhibitors (SSRI) fluoxetine, sertraline and citalopram have been investigated for their ability to activate two carbonic anhydrase (CA) isozymes, hCA I and hCA II, in parallel with two standard activators for which the X-ray structure (in complex with isozyme II) has been resolved: histamine and phenylalanine. All three SSRI activated both isozymes with potencies comparable to that of the standards although the profile was different: for hCA I, best activators were fluoxetine and histamine, with citalopram and sertraline showing weaker activity. For hCA II, the best activators were phenylalanine and citalopram, and the weakest histamine and sertraline, whereas fluoxetine showed an intermediate behavior. These results suggest that SSRI efficacy in major depression complicating Alzheimer's disease may be partly due to their ability to activate CA isozymes and may lead to the development of potent activators for the therapy of diseases associated with significant decreases in brain CA activity.

Brain↗

PubMed2003

Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with a bis-sulfonamide-two heads are better than one?

The X-ray crystal structure for the adduct of human carbonic anhydrase II (hCA II) with 4-(4-sulfamoylphenylcarboxamidoethyl)benzenesulfonamide, a topically acting antiglaucoma sulfonamide has been resolved at a resolution of 1.8 A. Its binding to the enzyme is similar with that of other sulfonamides, considering the interactions of the sulfonamide zinc anchoring group, but differs considerably when the organic part of the inhibitor is analyzed. This part of the inhibitor interacts only within the hydrophobic half of the CA active site, leaving the hydrophilic half able to accomodate several water molecules not present in the uncomplexed enzyme. Furthermore, the second head (sulfonamide moiety) participates in two strong hydrogen bonds with amino acid residues (Gly 132 and Gln 136) situated on the rim of the entrance to the active site cleft. Thus, the answer to the question in the title of this paper is that two heads are better than one, since the two sulfamoyl moieties of the inhibitor allow its proper orientation within the active site, with only one head binding in ionized form to the zinc ion, the organic part lying within the hydrophobic half of the active site, and the terminal, carboxamido containing phenylsulfamoyl head participating in strong hydrogen bonds with amino acid residues located at the entrance of it. All these findings are important for the design of better carboxamido CA inhibitors with applications in clinical medicine.

Amino Acids↗

PubMed2003

Carbonic anhydrase inhibitors. Inhibition of cytosolic isozymes I and II and transmembrane, tumor-associated isozyme IX with sulfamates including EMATE also acting as steroid sulfatase inhibitors.

A series of sulfamates or bis-sulfamates incorporating aliphatic, aromatic, polycyclic (steroidal), and sugar moieties in their molecules has been synthesized and assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of the cytosolic isozymes CA I andII, and the transmembrane, tumor-associated isozymes CA IX. Some of these compounds were previously reported to act as inhibitors of steroid sulfatases, among which estrone sulfatase (ES) and dehydroepiandrosterone sulfatase (DHEAS) are the key therapeutic targets for estrogen-dependent tumors. Very potent (nanomolar) inhibitors were detected against the three investigated CA isozymes. Best CA I inhibitors were phenylsulfamate and some of its 4-halogeno derivatives, as well as the aliphatic compound n-octyl sulfamate. Against CA II, low nanomolar inhibitors (1.1-5 nM) were phenylsulfamate and some of its 4-halogeno/nitro derivatives, n-octyl sulfamate, and estradiol 3,17beta-disulfamate among others. All the investigated sulfamates showed efficient CA IX inhibitory properties, with inhibition constants in the range of 18-63 nM. The best CA IX inhibitor detected so far was 4-chlorophenylsulfamate. These data are critical for the design of novel antitumor properties, mainly for hypoxic tumors that overexpress CA IX, which are nonresponsive to radiation or chemotherapy. The antitumor properties of the ES/DHEAS inhibitors in clinical trials may on the other hand also be due to their potent inhibitory properties of CA isozymes involved in tumorigenicity, such as CA II and CA IX.

Antigens, Neoplasm↗

PubMed2003

Carbonic anhydrase inhibitors: inhibition of cytosolic isozymes I and II with sulfamide derivatives.

A novel class of effective CAIs has been identified, starting from a very weak carbonic anhydrase inhibitor (CAI), sulfamide, whose X-ray crystal structure in the adduct with hCA II has recently been reported. A series of N,N-disubstituted- and N-substituted-sulfamides were prepared from the corresponding amines and N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide or the unstable N-(tert-butoxycarbonyl)sulfamoyl chloride. The disubstituted compounds being too bulky, were ineffective as CAIs, whereas mono-substituted derivatives (incorporating aliphatic, cyclic and aromatic moieties) as well as a bis-sulfamide, behaved as micro-nanomolar inhibitors of two cytosolic isozymes, hCA I and hCA II, responsible for critical physiological processes in higher vertebrates. Aryl-sulfamides were more effective than aliphatic derivatives. Low nanomolar inhibitors have been detected, which generally incorporated 4-substituted phenyl moieties in their molecule. This is the first example of CAIs in which low nanomolar inhibitors were generated starting from a very ineffective lead molecule.

Amines↗