Drug development process: combating pain
Drug development process: combating pain

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Drug development process: combating pain

2.3  Steroid drugs

Steroids were some of the earliest naturally produced endogenous structures discovered and they play an important part in many fields of medicine, including fertility and contraception, and the treatment of inflammation, asthma and cancer. They also have an important role to play in the treatment of ailments such as cardiovascular disease, infection, osteoporosis, trauma, as well as menstrual disorders and problems during the menopause.

Steroids have also been used as ‘spacer’ molecules in neuromuscular blockers and as carrier molecules for other drugs. The fact that steroids have such a diverse number of applications suggests that they have a ‘privileged scaffold’. This means that the physical and chemical properties of the steroid skeleton are such that there is a good chance that a substance having a similar structure will have the required pharmacokinetic properties to be an effective drug. For example, steroids are generally hydrophobic in nature and so they are able to pass through the cell membrane and reach potential targets such as enzymes and receptors within the cell.

The story of the discovery and development of steroids has similarities with that of the opioids in that it illustrates the traditional approaches used in medicinal chemistry before the era of genomics, proteomics, molecular modelling and in silico drug design. As with the opioids, active steroids were discovered long before their molecular targets in the body were identified. Therefore, drug research focused on the structure of the lead compound and concentrated on making various analogues to study how such changes altered the pharmacological properties. As in all areas of medicinal chemistry, modern techniques such as genomics, proteomics, X-ray crystallography and molecular modelling have served to provide new insights into how the steroids interact with receptors and enzymes, and to design new drugs based on that understanding.

Steroids are defined as having a particular tetracyclic skeleton involving three six-member rings and one five-member ring. Different steroids have different functional groups or substituents attached to this skeleton (for example alkyl groups, alcohols, ketones and halogens) or functional groups within the structure itself (for example an aromatic ring and/or alkene groups). Slight modifications in functional groups and substituents can have a dramatic effect on the pharmacological activity and selectivity of these compounds. This is one reason why steroids are such important hormones, and can have such a wide range of effects within the body. They are vital to numerous physiological processes including cell growth, sexual development, maintenance of salt balance and the control of sugar metabolism. Abnormalities in steroid biosynthesis, metabolism and receptor interactions all contribute to a variety of diseases. Steroids are not confined to human biochemistry. They are also found in animals, plants, and fungi. Steroids from other species have the same molecular tetracyclic scaffold as human steroids, but they have quite different functional groups and substituents.

The most common steroid present in the human body is cholesterol, which is crucial to the biosynthesis of the hormonal steroids that are present in much lower quantities. Cholesterol also plays an important structural role in cell membranes. Despite that, high cholesterol levels are a well-known problem that can lead to cardiovascular or cerebrovascular disease, and so cholesterol-lowering drugs such as the statins are some of the most important and profitable drugs produced by the pharmaceutical industry.

Steroids are not without controversy. Like all drugs, they can have unacceptable side-effects. Moreover, they are open to abuse; anabolic steroids were originally designed as a means of building up muscle in patients suffering from muscle-wasting diseases, but they have been a long-running problem in the sporting world, with athletes taking these agents in an attempt to produce better performances, despite the many risks associated with their usage and the doubtful benefits obtained.

The medicinal chemistry research behind steroids is vast, so it is important to concentrate on the steroids that are important, or have the potential to be important, in the treatment of inflammation and asthma. Their design is based on the glucocorticoids, which are produced in the adrenal medulla. Currently, the most common steroids used in medicine are beclometasone dipropionate, budenoside, ciclesonide, fluticasone propionate, mometasone furoate, triamcinolone acetonide, betamethasone, dexamethasone, flumetasone pivalate, flunisolide, deflazacort, methylprednisolone, prednisolone and hydrocortisone.

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