At least 14 different carbonic anhydrase (CA, EC 4.2.1.1) isoforms were isolated in higher vertebrates, where these zinc enzymes play crucial physiological roles. Some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII), others are membrane‐bound (CA IV, CA IX, CA XII, and CA XIV), CA V is mitochondrial and CA VI is secreted in saliva. Three acatalytic forms are also known, which are denominated CA related proteins (CARP), 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 as well as inorganic, metal complexing anions. The catalytic and inhibition mechanisms of these enzymes are understood in detail, and this helped the design of potent inhibitors, some of which possess important clinical applications. The use of such enzyme inhibitors 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: several potent sulfonamide inhibitors inhibited the growth of a multitude of tumor cells in vitro and in vivo, thus constituting interesting leads for developing novel antitumor therapies. Furthermore, some other classes of compounds that interact with CAs have recently been discovered, some of which possess modified sulfonamide or hydroxamate moieties. Some sulfonamides have also applications as diagnostic tools, in PET and MRI or as antiepileptics or for the treatment of other neurological disorders. Future prospects for drug design applications for inhibitors of these ubiquitous enzymes are also discussed. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 2, 146–189, 2003

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyse the interconversion between CO₂ and bicarbonate as well as other hydrolytic reactions. Among the six genetic families known to date, the α-, β-, γ-, δ-, ζ- and η-CAs, detailed kinetic and X-ray crystallographic studies have allowed a deep understanding of the structure–function relationship in this superfamily of proteins. A metal hydroxide nucleophilic species of the enzyme, and a unique active site architecture, with half of it hydrophilic and the opposing part hydrophobic, allow these enzymes to act as some of the most effective catalysts known in Nature. The CA activation and inhibition mechanisms are also known in detail, with a large number of new inhibitor classes being described in the last years. Apart from the zinc binders, some classes of inhibitors anchor to the metal ion coordinated nucleophile, others occlude the entrance of the active site cavity and more recently, compounds binding outside the active site were described. CA inhibition has therapeutic applications for drugs acting as diuretics, antiepileptics, antiglaucoma, antiobesity and antitumour agents. Targeting such enzymes from pathogens may lead to novel anti-infectives. Successful structure-based drug design campaigns allowed the discovery of highly isoform selective CA inhibitors (CAIs), which may lead to a new generation of drugs targeting these widespread enzymes. The use of CAs in CO₂ capture processes for mitigating the global temperature rise has also been investigated more recently.