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The development of COX2 inhibitors

Nature Reviews Drug Discovery volume 2, pages 179–191 (2003)Cite this article

Key Points

  • Prostaglandins are bioactive lipids that have potent actions in both pathological (inflammation, fever and pain) and physiological (protection of gastric mucosa, platelet agrregation) events.

  • Prostaglandins are formed enzymatically by the cyclooxygenase (COX1) enzyme from unesterified fatty acids, especially arachidonic acid.

  • The synthesis of prostaglandins is blocked by the aspirin-like drugs (NSAIDs) and this explains the therapeutic (anti-inflammatory, analgesic and antipyretic) actions of these drugs as well as their principal side effects (gastric damage and inhibition of platelet aggregation).

  • Early hints in the literature suggested that there may be more than one form of the enzyme and this was eventually confirmed when a second isoform (COX2) was discovered in increased amounts in inflammatory tissues.

  • It was suggested that the constitutive COX1 is the isozyme responsible for the physiological effects of prostaglandins in the stomach and in platelets, whereas the inducible COX2 was proposed as the main isoform responsible for inflammation.

  • Most of the pre-existing NSAIDs inhibited both isoforms, perhaps explaining why these drugs had both therapeutic and side effects. An intensive search was begun to find a selective COX2 inhibitor. This culminated in the introduction of a new class of anti-inflammatories — the COX2 selective inhibitors — with improved tolerance.

  • There may be other forms of COX that could account for some of the remaining discrepancies in action amongst NSAIDs.

Abstract

Aspirin, arguably the world's favourite drug, has been around since the late nineteenth century, but it wasn't until the late 1970s that its ability to inhibit prostaglandin production by the cyclooxygenase enzyme was identified as the basis of its therapeutic action. Early hints of a second form of the cyclooxygenase that was differentially sensitive to other aspirin-like drugs ultimately ushered in an exciting era of drug discovery, culminating in the introduction of an entirely new generation of anti-inflammatories. This article reviews the story of this discovery and looks at the future of cyclooxygenase pharmacology.

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Figure 1: An overview of prostaglandin synthesis and metabolism.
Figure 2: Chemical structures of NSAIDs and related compounds.
Figure 3: Chemical structures of NSAIDs and related compounds.
Figure 4: Comparison of the NSAID binding sites of COX1 and COX2 after Browner.
Figure 5: Some key residues in COX1 and COX2.

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Acknowledgements

R.J.F. is a Principal Fellow of the Wellcome Trust. The author wishes to thank T. Warner for reviewing the manuscript and for making constructive suggestions.

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  1. Department of Biochemical Pharmacology, The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK

    Rod J. Flower

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DATABASES

Online Mendelian Inheritance in Man

Epidermal growth factor

interleukin-1

osteoarthritis

rheumatoid arthritis

Glossary

ISOZYME (ISOENZYME)

One of several forms of an enzyme in an individual or population that catalyse the same reaction but differ from each other in such properties as substrate affinity and maximum rates of enzyme–substrate reaction.

ANTIPYRETIC

Describes the fever-suppressive activity of a drug.

HYPERALGESIA

An abnormal state of increased sensitivity to painful stimuli.

ENANTIOMERS

A pair of compounds whose molecular structures are mirror images of each other.

CONTRALATERAL

On or affecting the opposite side.

HOUSEKEEPING GENE

A gene that is usually expressed at a fairly constant rate in cells as it subserves some constant physiological requirement. By comparison, an inducible gene is one that normally appears at a very specific time and in response to a specific stimulus.

SYNOVIAL TISSUE

The tissues that surround the joints.

CARRAGEENAN

A sulphated cell-wall polysaccharide that is found in certain red algae, which contains repeating sulphated disaccharides of galactose, and sometimes anhydrogalactose, and is used to induce an inflammatory lesion when injected into experimental animals.

DYSMENORRHOEA

Painful menstruation, often associated with nausea, vomiting, headache and faintness. It is thought to be related to excessive prostaglandin production.

MACULA DENSA

Part of the juxtaglomerular apparatus of the kidney that is important in sensing changes in blood pressure.

IC50 VALUE

The concentration of a drug or substance that inhibits a particular effect by 50%.

APOPTOTIC

A term used to describe the state of programmed cell death.

RT-PCR

(Reverse transcription polymerase chain reaction). A technique that is used to amplify cDNA from an mRNA template using sequence-specific primers.

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Flower, R. The development of COX2 inhibitors. Nat Rev Drug Discov 2, 179–191 (2003). https://doi.org/10.1038/nrd1034

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