History of Cortisone and Related Compounds

Abstract

Steroidal hormones were isolated from the adrenal cortex in the 1930s and were synthesised a decade later. Several of these structures have highly effective anti‐inflammatory activity but also exhibit serious side effects. Chemical analogues have now been discovered with better activity and reduced side effects. Such agents are administered for the treatment of a wide range of inflammatory conditions, including rheumatoid arthritis and asthma. Anti‐inflammatory activity can be improved by introducing functional groups or substituents at key positions of the steroid structure. Similarly, substituents placed at key positions can reduce side effects and metabolic susceptibility. Nevertheless, there are still risks associated with the long‐term use of steroids, and research is currently looking at novel agents that will act locally at the site of administration and are rapidly metabolised to inactive compounds once they reach the blood supply.

Key Concepts:

  • Adrenocorticoids are released by the adrenal glands and can be classified as glucocorticoids or mineralocorticoids.

  • Cortisone, hydrocortisone and corticosterone are examples of glucocorticoids.

  • Cortisone was isolated in the late 1930s, and a synthesis was devised in 1948.

  • The beneficial anti‐inflammatory effects of cortisone on patients with rheumatoid arthritis were demonstrated in the late 1940s.

  • Glucocorticoids have important effects on cell metabolism and are released as a result of stress.

  • Several glucocorticoids have anti‐inflammatory activity making them useful in the treatment of conditions such as skin and mucosal inflammations, rheumatoid arthritis and asthma.

  • Endogenous glucocorticoids such as cortisol and cortisone are used in the clinic but suffer from side effects.

  • Analogues of cortisone and cortisol have been developed that have improved anti‐inflammatory activity and reduced side effects.

  • Key structural features have been identified that can be introduced to the steroid structure in order to increase anti‐inflammatory activity and absorption, while decreasing side effects and metabolism.

  • Soft drugs have been developed since the 1970s, which act locally at the site of administration and are rapidly metabolised should they reach the blood supply.

Keywords: hormones; corticosteroids; anti‐inflammatories; rheumatoid arthritis; asthma; glucocorticoids; soft drugs; cortisone; Philip Hench; Edward Kendall; Lewis Sarett

Figure 1.

Endogenous adrenocorticoids. Modified from Figure CS6.2 and CS6.3 reference Patrick .

Figure 2.

Structural features present in cortisone. Modified from Figure CS6.1 reference Patrick .

Figure 3.

Synthetic analogues of cortisone. Modified from Figure CS6.3 reference Patrick .

Figure 4.

Cortisone analogues with good skin and mucosal absorption. Modified from reference CS6.4, 6.5 and 6.9 Patrick .

Figure 5.

Metabolism of cortisol to inactive cortienic acid. Reproduced from Figure CS6.11 reference Patrick .

Figure 6.

‘Soft drugs’ used in opththalmology. Modified from Figure CS6.12 and CS6.14 reference Patrick .

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References

Biggadike K, Uings I and Farrow SN (2004) Designing corticosteroid drugs for pulmonary selectivity. Proceedings of the American Thoracic Society 1: 352–355.

Bodor N and Buchwald P (2002) Design and development of a soft corticosteroid, loteprednol etabonate. In: Schleimer RP, O'Byrne PM, Szefler SJ and Brattsand R (eds) Inhaled Steroids in Asthma. Optimizing Effects in the Airways, pp. 541–564. New York, NY: Marcel Dekker.

Kurucz I, Toth S, Nemeth K et al. (2003) Potency and specificity of the pharmacological action of a new, antiasthmatic, topically administered soft steroid, etiprednol dicloacetate (BNP‐166). Journal of Pharmacology and Experimental Therapeutics 307: 83–92.

Patrick GL (2013) An Introduction to Medicinal Chemistry, pp. 689–699. Oxford, UK: Oxford University Press.

Ramaa CS, Mohan R, Mundada AS and Kadam VJ (2008) Retrometabolism based drug targeting – soft drug approach. Indian Journal of Chemistry 47B: 721–733.

Sneader W (1985) Drug Discovery: The Evolution of Modern Medicines. Chichester, UK: John Wiley and Sons Ltd.

Further Reading

Glyn JH (1998) The discovery and early use of cortisone. Journal of the Royal Society of Medicine 91(10): 513–517.

Quirke V (2005) Making British cortisone. Glaxo and the development of corticosteroids in Britain in the 1950s–1960s. Studies in History and Philosophy of Biological and Biomedical Studies 36: 645–674.

Rooke TW (2012) The Quest of Cortisone. East Lansing: Michigan State University Press.

Slater LB (2000) Industry and academy. The synthesis of steroids. Historical Studies in the Physical and Biological Studies 30(2): 443–480.

Sneader W (1996) Drug Prototypes and their Exploitation, pp. 343–360. Chichester, UK: John Wiley.

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Patrick, Graham(Mar 2013) History of Cortisone and Related Compounds. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003627.pub2]