Carbonic anhydrases: novel therapeutic applications for inhibitors and activators
Top Cited Papers
- 1 February 2008
- journal article
- review article
- Published by Springer Nature in Nature Reviews Drug Discovery
- Vol. 7 (2) , 168-181
Abstract
Carbonic anhydrases (CAs) are widespread enzymes in bacteria, archaea and eukaryotes, and catalyze a crucially important physiological reaction: the hydration of carbon dioxide to bicarbonate and protons. These enzymes are inhibited by several classes of compounds, such as sulphonamides, sulphamates and sulphamides, among others. The inhibitors bind to the catalytic zinc ion within the enzyme cavity. Several such derivatives are clinically used inhibitors, such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, topiramate, zonisamide, sulpiride, sukthiame, celecoxib and valdecoxib among others. Several compounds are in clinical development, such as indisulam and COUMATE-667. CA inhibitors (CAIs) are used in therapy as diuretic and antiglaucoma agents but also show anti-obesity and antitumour effects. Some compounds are in clinical development for such applications (obesity and cancer). Most CAIs that are currently available show undesired side effects due to indiscriminate inhibition of CA isoforms other than the target one. Many new CAIs are developed in the search of isozyme-selective compounds as potential drugs with fewer side effects. Bacterial, fungal and protozoan CAs present in many pathogens have recently been considered as potential targets for the development of inhibitors with therapeutic applications. CA activators (CAAs) participate in the enzyme catalytic cycle by facilitating the rate-determining step: a release of a proton from the zinc-coordinated water molecule to the reaction medium. CAAs from various classes of compounds were developed in the past and characterized by means of X-ray crystallography and kinetic measurements. Such derivatives may lead to the development of anti-Alzheimer's disease agents and therapies to enhance memory.Keywords
This publication has 118 references indexed in Scilit:
- Carbonic anhydrase inhibitors: The β-carbonic anhydrase from Helicobacter pylori is a new target for sulfonamide and sulfamate inhibitorsBioorganic & Medicinal Chemistry Letters, 2007
- Oxygen, a source of life and stressFEBS Letters, 2007
- Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancerBritish Journal of Cancer, 2007
- Carbonic Anhydrase Inhibitors. DNA Cloning, Characterization, and Inhibition Studies of the Human Secretory Isoform VI, a New Target for Sulfonamide and Sulfamate InhibitorsJournal of Medicinal Chemistry, 2006
- Carbonic Anhydrase Inhibitors: Clash with Ala65 as a Means for Designing Inhibitors with Low Affinity for the Ubiquitous Isozyme II, Exemplified by the Crystal Structure of the Topiramate Sulfamide AnalogueJournal of Medicinal Chemistry, 2006
- Carbonic anhydrase inhibitors: Inhibition of the transmembrane isozyme XIV with sulfonamidesBioorganic & Medicinal Chemistry Letters, 2005
- Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isozyme VII with aromatic and heterocyclic sulfonamidesBioorganic & Medicinal Chemistry Letters, 2005
- Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides derived from 4-isothiocyanato-benzolamideBioorganic & Medicinal Chemistry Letters, 2004
- Hypoxia activates the capacity of tumor‐associated carbonic anhydrase IX to acidify extracellular pHFEBS Letters, 2004
- Structural basis for the recognition of hydroxyproline in HIF-1α by pVHLNature, 2002