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Science: Chemists tame the wild side of drugs

Science: Chemists tame the wild side of drugs

作者:练糁  时间:2019-02-26 08:10:00  人气:

By JOHN EMSLEY IN THE US, chemists have found a way of making many common drugs much more safe and effective. The process involves converting the inactive portion of a drug – half its bulk – into the biologically active form. Already, the researchers have proved that their process works for ibuprofen and naproxen, anti-inflammatory drugs that are used widely to treat rheumatoid arthritis. Ichiro Shinkai, Robert Larsen and their colleagues at the American pharmaceuticals company Merck Sharp and Dohme, have experimented with drugs that consist of a so-called chiral mixture – the right- and left-handed forms of a molecule. The two molecular forms – mirror-images of each other, which chemists label the R and S forms – each make up half of the drug. Of the 1800 drugs currently available to doctors, about half are chiral mixtures. Generally, in a drug, only one form is active in treating a medical condition. For ibuprofen and naproxen, for example, it is the S form. Using their technique, Larsen and his colleagues can produce ibuprofen which consists of more than 99 per cent the S-form (Journal of the American Chemical Society, vol 111, p 7650). At present, pharmaceuticals companies throughout the world are under pressure from the authorities that regulate drugs to supply all drugs in the pure, active form. The reason for this is that there is always a danger that both chiral forms of a drug may be biologically active, one in a way that is not intended by the drug maker. This was most tragically demonstrated in the case of the drug thalidomide, which doctors prescribed 30 years ago to pregnant women to prevent morning sickness. Although the S-form of the drug performed its function very well, R-thalidomide – unknown to doctors – was capable of deforming the limbs of fetuses. Larsen and his colleagues have devised a method to purify ibuprofen and naproxen – both derivatives of phenylpropionic acid – which involves several stages. The chemists react the chiral mixture with a compound called thionyl chloride, then another called trimethylamine. This results in a ketene molecule, which is identical, irrespective of whether it is derived from the R or S form of the drug. Next, the chemists react the ketene with ethyl lactate, a natural a-hydroxy ester, which occurs in the pure S form. This produces a derivative of ibuprofen, which is itself also a pure mirror image form. When the chemists treat this derivative with acid, the ethyl lactate is removed to leave pure S-ibuprofen. The key ingredient of Larsen’s method is the solvent in which the reaction with ethyl lactate takes place. This must be a hydrocarbon solvent such as hexane, heptane or toluene. So far, no country has banned existing drugs that are chiral mixtures. However, after 1992, the US Food and Drug Adminis tration will insist that pharma ceuticals companies in the US prove not only that the active form of a drug is safe and effective, but that the chiral form is completely harmless. Confronted by such legislation,