IngentaConnect Single-Isomer Drugs: True Therapeutic Advances

Abstract:

Chirality is one of the main features of biology, and many of the processes essential for life are stereospecific, meaning that one out of two or more isomers may work best in a particular physiological situation. Could this be used in drug development and result in any clinical relevance and true therapeutic advance? There are occasions when the development of one of the isomers might be expected to be advantageous: for example, only one of the isomers may be active, only one of the isomers may cause adverse effects, or one of the isomers may have more advantageous pharmacological properties. As an example of the last, the successful development of esomeprazole will be described.

Before the introduction of esomeprazole, the proton pump inhibitor omeprazole was the standard treatment for gastric acid-related diseases, such as gastro-oesophageal reflux disease. A serious type of gastro-oesophageal reflux disease is erosive oesophagitis, an increasingly common condition that may lead to life-threatening complications. Doubling the standard dose of omeprazole from 20 to 40mg did not improve healing rates (74% versus 75%), and thus a substantial proportion of patients remained unhealed with standard treatment.

The (S)-isomer of omeprazole, esomeprazole, was shown to heal more patients than omeprazole as a result of unique metabolic properties that clearly differentiates esomeprazole from omeprazole, the racemate. At comparable doses, these properties lead to several clinical advantages: higher bioavailability in extensive metabolisers (the majority of patients), lower exposure in poor metabolisers, less interindividual variation and a steeper dose-response curve at steady state resulting in a more pronounced inhibition of gastric acid secretion. Esomeprazole has been studied clinically for a variety of acid-related conditions, showing that the compound is as well tolerated and more effective with regard to healing and symptom relief than the recommended treatment with omeprazole.

Thus, from this example it is clear that the exploration and development of single-isomer drugs may bring significant advances in treatment options.

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