title: Diuretics with carbonic anhydrase inhibitory action: a patent and literature review (2005 - 2013).
abstract: BACKGROUND
  The benzothiadiazines and high ceiling diuretics (hydrochlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide) contain primary sulfamoyl moieties acting as zinc-binding groups in the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). These drugs are widely used clinically and were recently shown to weakly inhibit isoforms CA I and II, but to possess stronger activity against isoforms involved in other important pathologies, for example, obesity, cancer, epilepsy and hypertension.
  
  
  METHODS
  The class of clinically used diuretics, with CA inhibitory properties, is the main topic of the review. A patent literature review covering the period from 2005 to 2013 is presented.
  
  
  CONCLUSIONS
  This section presents an overview of the patent literature in the sulfonamide diuretic field. Most of the patents deal with the combination of diuretic sulfonamide CA inhibitors with other agents useful in the management of cardiovascular diseases and obesity. Such combinations exert a better therapeutic activity compared to similar diuretics that do not inhibit CAs, raising the question of the polypharmacological and drug repositioning effects of these old drugs. These effects seem to be due to the potent inhibition of such drugs against CA isoforms present in kidneys and blood vessels, which explain both the blood pressure lowering effects as well as organ-protective activity of the drugs. An explanation of these data is provided by the fact that inhibition of the renal CAs leads to a large increase of the nitrite excretion in urine, suggesting that renal CAs are involved in nitrite reabsorption in humans. Important lessons for the drug design of sulfonamide CA inhibitors (CAIs) can be drawn from these data.
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002256:Carbonic Anhydrases / Q000187:drug effects* / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D007668:Kidney / Q000201:enzymology; D010330:Patents as Topic; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D004232:Diuretics; D013449:Sulfonamides; D002256:Carbonic Anhydrases