Drugs, chromonics

Cromolyn sodium (Intal) and nedocromil sodium (Tilade) are chemically related drugs called chromones that are used for the prophylaxis of mild or moderate asthma. Both are administered by inhalation and have... 

The chromone cromolyn sodium (5-5) was at one time considered the forerunner of a novel class of antiallergic and antiasthmatic drugs that act at one of the earliest stages of the allergic reaction. Detailed experiments, acmally conducted after the dmg s clinical effectiveness had been confirmed, suggested that the compound inhibited the release of mediators of the allergic reaction from mast cells. The dmg is not very active when taken orally and is usually applied topically to the lung by insufflation as its sodium salt. Considerable efforts to uncover additional structurally related mediator release inhibitors have had only limited success. 

Methylesculetol-6,7-dinicotinate (32) is useful as an antiinflammatory and vasodilator oflow toxicity (101). The synthesis of asarone [5555-15-1] (2,4,5-trimethoxy-l-propenylbenzene), which is used as a tranquilizer, has been patented (102). It occurs in calamus root, Acorns calamus L.y and is a chemosterilant for insects (103). 6,7-Dihydroxycoumarin-4-methylsulfonic acid and its salts are useful in the treatment of capillary permeability and fragility and for protecting oxidizable metabolites and drugs against biooxidation (104). Certain chromones derived from hydroxyhydroquinone, eg (33), and its salts, esters, and amides are valuable in the prophylactic treatment of asthma (105) (see Antiasthmatic agents). 2-Methoxy-6-multiprenyl-l,4-benzoquinones are intermediates in the microbiological synthesis of coenzyme Q compounds (106). 

Other examples of twin drugs are the antioxidant probucol, which lowers the cholesterol level in blood, and cromolyn, a chromone heterocycle, which is useful in the inhalational treatment of bronchial asthma (Fig. 1.11). 

Heterocycles such as 4-trifluoromethylimidazole, phenoxazine, 3-formyl-chromone, coumarin derivatives, and vitamin K2 derivatives were investigated for their cytotoxicity against human normal and tumor cells. These compounds induced moderate tumor-specific cytotoxicity. VitaminK2 derivatives and prenylalcohols displayed disappointingly low tumor-specific cytotoxicity, although they have been reported to induce apoptosis-inducing activity. Human oral squamous cell carcinoma cell lines showed considerable variation in drug sensitivity. The type of cell death induced depended both on which types of cells and which inducers were used. 

The chromone group (e.g. sodium cromoglycate and nedocromil) are important antiallergic and antiinflammatory drugs, as well as antiasthmics and other uses, though their mode of action is imperfecfly understood. 

Figure 22. Examples of drug and dye molecules forming chromonic mesophases in water.

The natural compound khellin generated two families of cardioactive drugs on one side the benzopyrones, illustrated by the 3-methyl-chromone and chromonar (carbochromen), on the other side the benzofurans, illus-... 

Even though various antileukotriene drugs have been synthesized, none has reached clinical acceptability. Inhibition of histamine release by an apparent mast cell stabilizing mechanism (in lung tissue, but probably not elsewhere) is achieved with the carboxy-chromone derivative cromolyn sodium. The mechanism is believed to involve inhibition of histamine release from pulmonary mast cells by blocking Ca2+ movement through membrane channels. 

The main constituents of flavonoid drugs are 2-phenyl-y-benzopyrones (2-phenyl chromones) or structurally related, mostly phenolic, compounds. 

As our primary test model we initially decided that we had to stay with the rat PCA screen. However, since we were now interested in orally effective compounds we studied the activity of the chromones following their administration either directly into the stomach or into the intestine of the animals, the latter following anaesthetisation and laparotomy. Experience showed that the results obtained on intra-duodenal dosing were much more reproducible than those obtained by straight oral dosing and so for a number of years we have used this route of drug administration to determine the likely oral activity of our compounds. 

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