Carbonic anhydrase inhibitors methazolamide

Not all drugs contain functional groups that lend themselves readily to prodrug derivatization. A case in point is the carbonic anhydrase inhibitors such as acetazolamide, ethoxzolamide, and methazolamide. Although the amino functional group of their sulfonamide moiety can be methylated, the resulting analogs... 

Orally administered carbonic anhydrase inhibitors lower the intraocular pressure of glaucoma patients, however they induce a number of intolerable side effects associated with extraocular inhibition of the enzyme [5,6]. Thus, much research has been directed towards the search for a topically effective agent. Several compounds have been synthesized since the 1980 s in Merck Sharp Dohme Research Laboratories, and have been found to be topically active in man [7]. Unfortunately, many of these compounds were not very soluble. Attempts to obtain an active carbonic anhydrase inhibitor with good solubility resulted in the synthesis of Dorzolamide hydrochloride [8,9], which was first made available for pharmacological evaluation in 1987. Like other carbonic anhydrase inhibitors sulfonamides (such as acetazolamide, ethoxzolaniide, and methazolamide) dorzolamide is an inhibitor of human carbonic anhydrase isoenzymes I, II, and IV. In contrast to the other sulfonamides, dorzolamide is a potent inhibitor of isoenzymes II and IV, and a weak inhibitor of isoenzyme I [ 10]. Isoenzyme II is thought to play a major role in aqueous humor secretion. 

Alprazolam may also relieve tremor at doses of 0.75 to 3 mg/day (357). Because chronic use can lead to habituation or dependence, alprazolam is best used episodically for patients who require only intermittent tremor reduction to prevent social embarrassment or occupational interference. Methazolamide, a carbonic anhydrase inhibitor, has been reported to reduce hand tremor (at doses of 50 to 300 mg/day) in several open studies ( 358, 359). A controlled trial, however, could not confirm the efficacy of this agent in the treatment of tremor but did report that side effects such as paresthesias, sedation, headache, and gastrointestinal symptoms were common (77, 356). 

Acetazolamide (225) and methazolamide (226) are two carbonic anhydrase inhibitors which can be derivatized by Mannich-type derivatives to increase their solubility. Under physiological conditions the parent compound is regenerated (71JMC458). Cefazolin (227) is a thiadiazole analog of cephalosporanic acid useful as an antibacterial (70MI42701). 

The carbonic anhydrase inhibitors, of which acetazol-amide (rINN), a non-competitive inhibitor, is the prototype, are not suitable for normal diuretic use, because tolerance soon develops. However, they are well suited to brief intermittent use, particularly in the relief of glaucoma and in the prevention of acute mountain sickness. Acetazolamide and methazolamide (rINN) should be used with caution in the long-term control of glaucoma because of its serious systemic adverse effects. However, brinzolamide (rINN) and dorzolamide (rINN) are available for long-term topical administration. 

The carbonic anhydrase inhibitors include acetazolamide, dichlorphenamide, ethoxzolamide and methazolamide. 

A number of carbonic anhydrase inhibitors have been used topically, including dichlorphenamide (diclofenamide) and methazolamide. These are diuretics used systemically, and the diuretic mannitol is sometimes used in emergencies. 

Inhibitors to the enzyme carbonic anhydrase. This enzyme is widely distributed in the body and has a fundamental role in the control of acid-base balance. In the 1920s it was noticed that the SULPHONAMIDE sulfanilamide had a weak diuretic action. Acetazolamide is a subsequent thiadiazole-sulphonamide derivative with potent carbonic anhydrase inhibitor activity. Clinically, it is used for antiglaucoma TREATMENT, is a weak diuretic and can be used to treat mountain sickness. Dichlorphenamide and dorzolamide are sulphonamide derivatives also used for antiglaucoma treatment. Methazolamide is used as a diuretic. Now that seven or more isoenzymes of carbonic anhydrase have been cloned. Isolated and mapped, some new initiatives are aimed at developing agents with more selective actions. 

Figure 15. Chemical structures of the carbonic anhydrase inhibitors 15-21. The small aromatic sulfonamides 15 and 16 bind with nanomolar affinity to carbonic anhydrase. Methazolamide 18 was used for a long time to treat glaucoma. 19 was the first topically active inhibitor. Structure-based drug design at Merck first led to 20 and then to the marketed drug, dorzolamide 21.

When sulfanilamide was introdnced as a chemotherapeutic agent, metabolic acidosis was recognized as a side effect. This observation led to the demonstration that snl-fanilamide is an inhibitor of carbonic anhydrase. Snbse-quently, an enormous number of sulfonamides were synthesized and tested for the ability to inhibit carbonic anhydrase of these componnds, acetazolamide has been studied most extensively. Three carbonic anhydrase inhibitors currently are available in the United States—acetazolamide, dichlorphenamide (Daranide), and methazolamide (GlaucTabs). The common molecnlar motif of available carbonic anhydrase inhibitors is an nnsnbstitnted sulfonamide moiety. 

Methazolamide (50 to 100 mg p.o. b.i.d. or t.i.d.), a carbonic anhydrase inhibitor, decreases the formation of aqneons humor, lowering lOP, and hence is indicated as an adjunctive treatment for the treatment of open-angle glancoma. Methazolamide is absorbed orally, and distribntes into plasma, erythrocytes, extracellular fluid, bile, aqueous humor, and granulocyte colony-stimulating factor (CSF). It is metabolized partially in the liver and is partially (20 to 30%) excreted in the urine. 

Acetazolamide, Methazolamide, Diclofenamide and Disulfamide and potent carbonic anhydrase inhibitors employed as diureties. Discuss the struetural difference amongst these drugs and give the synthesis of any two eompoimds. 

Methazolamide is a derivative of acetazolamide in which one of the active hydrogens has been replaced by a methyl group. This decreases the polarity and permits a greater penetration into the ocular fluid, where it acts as a carbonic anhydrase inhibitor, reducing intraocular pressure. Its dose for glaucoma is 50 to 100 mg two to three... 

Carbonic anhydrase inhibitors include acetazolamide (Diamox), dichlor-phenamide (Damide, Oratrol), and methazolamide (Neptazane). 

Potassium-depleting diuretics Carbonic anhydrase inhibitors Acetazoiamide, Diciofenamide (Dichiorphenamide), Methazolamide... 

However, in the study of these compounds, other applications were acquired. The occurrence of carbonic anhydrase, as a functionally important enzyme in the eye and in the central nervous system, led to the use of the inhibitors to treat glaucoma and epilepsy. Methazolamide has certain advantages due to greater penetration and intracellular distribution (17) its principal use is in the treatment of glaucoma. 

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