Novel Therapeutic Applications for Inhibitors and Activators
Total Page：16
File Type：pdf, Size：1020Kb
REVIEWS Carbonic anhydrases: novel therapeutic applications for inhibitors and activators Claudiu T. Supuran Abstract | Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens. In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that CAIs could have potential as novel anti-obesity, anticancer and anti-infective drugs. Furthermore, recent studies suggest that CA activation may provide a novel therapy for Alzheimer’s disease. This article discusses the biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases, and highlights progress in the development of specific modulators of the relevant CA isoforms, some of which are now being evaluated in clinical trials. Carbonic anhydrases (CAs; also known as carbonate Many of the CA isozymes involved in these processes Glaucoma A chronic, degenerative eye dehydratases EC 4.2.1.1) are ubiquitous metalloenzymes are important therapeutic targets with the potential to be disease, characterized by high present in prokaryotes and eukaryotes that are encoded inhibited to treat a range of disorders including oedema, intraocular pressure that by four evolutionarily unrelated gene families. These are glaucoma, obesity, cancer, epilepsy and osteoporosis. causes irreversible damage to the α‑CAs (present in vertebrates, bacteria, algae and Two main classes of CA inhibitors (CAIs) are known: the optic nerve head, resulting in the progressive loss of cytoplasm of green plants); the β‑CAs (predominantly the metal‑complexing anions and the unsubstituted visual function and eventually in bacteria, algae and chloroplasts of monodicotyle‑ sulphonamides and their bioisosteres — for example, blindness. dons and dicotyledons); the γ‑CAs (mainly in archaea sulphamates and sulphamides compounds 1–25 (FIG. 1; and some bacteria); and the δ‑CAs (present in some TABLE 1). These inhibitors bind to the Zn2+ ion of the marine diatoms)1–7. In mammals, 16 α‑CA isozymes or enzyme either by substituting the non‑protein zinc CA‑related proteins have been described (TABLE 1), with ligand to generate a tetrahedral adduct or by addition different catalytic activity, subcellular localization and to the metal coordination sphere to generate a trigonal‑ tissue distribution8–18. There are five cytosolic forms (CA I, bipyramidal species1–7 (FIG. 2). At least 25 clinically used CA II, CA III, CA VII and CA XIII), five membrane‑ drugs have been reported to possess significant CA bound isozymes (CA IV, CA IX, CA XII, CA XIV and inhibitory properties (discussed below), in addition to CA XV), two mitochondrial forms (CA VA and CA VB), many other derivatives belonging to the sulphonamide, and a secreted CA isozyme (CA VI)19–25. sulphamate or sulphamide families1–3,5,7,8,19–25. CAs catalyse a simple physiological reaction (BOX 1): Furthermore, the potential use of CAIs to fight infec‑ the conversion of CO2 to the bicarbonate ion and pro‑ tions caused by protozoa, fungi and bacteria has recently Laboratorio di Chimica tons. The active site of most CAs contains a zinc ion emerged as a new research direction. CAs belonging Bioinorganica, Università 2+ degli Studi di Firenze, (Zn ), which is essential for catalysis. The CA reaction to various families were cloned and characterized in Rm 188, Via della is involved in many physiological and pathological pro‑ many such organisms (such as Plasmodium falciparum, Lastruccia 3, I-50019 Sesto cesses, including respiration and transport of CO2 and Helicobacter pylori, Mycobacterium tuberculosis, Fiorentino (Firenze), Italy. bicarbonate between metabolizing tissues and lungs; Candida albicans and Cryptococcus neoformans)26–34 and e-mail: pH and CO homeostasis; electrolyte secretion in vari‑ have been shown to be crucial for the virulence, growth [email protected] 2 doi:10.1038/nrd2467 ous tissues and organs; biosynthetic reactions (such as or acclimatization of the parasite. In addition, impor‑ Published online gluconeogenesis, lipogenesis and ureagenesis); bone tant advances have been achieved in the understanding 2 January 2008 resorption; calcification; and tumorigenicity8–18. of CA activation by several classes of activators35–41. 168 | febRUARY 2008 | voLUme 7 www.nature.com/reviews/drugdisc © 2008 Nature Publishing Group REVIEWS Table 1 | Inhibition data with selected sulphonamides/sulphamates/sulphamides 1–25 against isozymes I–XIV* KI Isozyme (h = human, m = mouse) (nm) hCA I‡ hCA II‡ hCA III‡ hCA IV‡ hCA VA‡ hCA VB‡ hCA VI‡ hCA VII‡ hCA IX§ hCA XII§ mCA XIII‡ hCA XIV‡ 1 250 12 2 × 105 74 63 54 11 2.5 25 5.7 17 41 2 50 14 7 × 105 6,200 65 62 10 2.1 27 3.4 19 43 3 25 8 1 × 106 93 25 19 43 0.8 34 22 50 2.5 4 374 9 6.3 × 105 95 81 91 134 6 43 56 1,450 1,540 5 1,200 38 6.8 × 105 15,000 630 21 79 26 50 50 23 345 6 50,000 9 7.7 × 105 8,500 42 33 10 3.5 52 3.5 18 27 7 45,000 3 1.1 × 105 3,950 50 30 0.9 2.8 37 3.0 10 24 8 31 15 10,400 65 79 23 47 122 24 3.4 11 106 9 250 10 7.8 × 105 4,900 63 30 45 0.9 58|| 3.8 47 1,460 10 56 35 2.2 × 106 8,590 20 6,033 89 117 5.1 11,000 430 5,250 11 12,000 40 10,600 6.5 × 105 174 18 0.8 3,630 46 3.9 295 110 12 3,450 21 7.0 × 105 24 765 720 653 23 34 12 1,050 755 13 37 10 6.5 × 105 NT NT NT NT NT 30 7.5 NT NT 14 50,000 21 7.4 × 104 880 794 93 94 2,170 16 18 98 689 15 54,000 43 7.8 × 104 1,340 912 88 572 3,900 27 13 425 107 16 18,540 5,950 1.0 × 106 7,920 10,060 7,210 935 10 103 633 12,100 773 17 1,300 45 1.3 × 106 650 134 76 145 18 24 5 76 33 18 4,000 21 3.1 × 105 60 88 70 65 15 14 7 21 13 19a 328 290 7.9 × 105 427 4,225 603 3,655 5,010 367 355 3,885 4,105 20 35,000 1,260 NT NT NT NT NT NT NT NT NT NT 21 54,000 2,000 6.1 × 105 216 750 312 1,714 2.1 320 5.4 15 5,432 22 348 138 1.1 × 104 196 917 9 1,347 2.8 23 4.5 15 4,130 23 51,900 2,520 2.3 × 105 213 890 274 1,606 0.23 36 10 13 4,950 24 62 65 3.2 × 106 564 499 322 245 513 420 261 550 52 25 4,930 6,980 3.4 × 106 303 700 NT NT NT 25.8 21.2 2,570 250 *The isoforms CA VIII, X and XI are devoid of catalytic activity and probably do not bind sulphonamides as they do not contain Zn2+ ions. ‡Full-length enzyme. §Catalytic domain. ||The data against the full-length enzyme is of 1,590 nM. NT, not tested, data not available. Such compounds might lead to pharmacological agents compounds 19a–e, as well as derivatives 20–25 are still that have the potential to treat Alzheimer’s disease, ageing widely clinically used2,3 (FIG. 1). However, some of these and other conditions involving memory deficits40. enzyme inhibitors could also be used for the systemic treatment of glaucoma (see below), and more recently, Carbonic anhydrase inhibitors newer derivatives have been discovered that have the CAIs include the classical inhibitors acetazolamide (com‑ potential as topical antiglaucoma agents, as well as anti‑ pound 1), methazolamide (compound 2), ethoxzolamide tumour, anti‑obesity or anti‑infective drugs1–3,5,7,9–26. (compound 3), sulthiame (compound 4) and dichloro‑ The inhibitory effects of some of these clinically phenamide (compound 5). CAIs also include more used drugs against the mammalian isoforms CA I–XIV recent drugs/investigational agents such as dorzolamide — of human or mouse origin — are shown in TABLE 1. (compound 6), brinzolamide (compound 7), indisulam As specific isozymes are responsible for different bio‑ (compound 8), topiramate (compound 9), zonisamide logical responses, the diverse inhibition profiles of the (compound 10), sulpiride (compound 11), COUMATE various isozymes may explain the different actual and (compound 12), EMATE (compound 13), celecoxib potential clinical applications of the CAIs, which range (compound 14), valdecoxib (compound 15) and saccharin from diuretics and antiglaucoma agents, to anticancer, (compound 16) (FIG. 1; TABLE 1). Derivatives 17 and 18 are anti‑obesity and anti‑epileptic drugs. However, a crucial investigational agents for targeting the tumour‑associated problem in CAI design is related to the high number of isoform CA IX (see later in the text). Many of these isoforms, their diffuse localization in many tissues and compounds were initially developed years ago during organs (TABLE 2), and the lack of isozyme selectivity of the search for diuretics, among which the thiazides, the presently available inhibitors. It can be observed that NatURE RevieWS | DRUG DISCOVERY voLUme 7 | febRUARY 2008 | 169 © 2008 Nature Publishing Group REVIEWS Box 1 | Mechanism of action of carbonic anhydrases there are sulphonamide‑ and sulphamate‑avid isoforms, such as CA II, VI, VII, IX, XII and XIII, which generally Carbonic anhydrases (CAs) catalyse the following reaction: show low nanomolar affinity for most of these inhibitors.