New method weeds out flipping drugs

A NEW method has been developed to help drug developers weed out compounds that could potentially transform into harmful versions of themselves once inside the human body. One pharmaceutical major is already working to implement the tool.

Researchers from the UK’s Cardiff and Liverpool John Moores Universities, working with AstraZeneca, have developed what they describe as a world-first quantitative risk assessment tool to assess the likelihood of an ingested drug undergoing racemisation, a process where a pure form of an active drug can ‘flip’ to form a mixture of its enantiomers.

Enantiomers are molecules that are mirror images of each other and are non-superimposable. Drug compounds can often exist in both these ‘right’- and ‘left’-handed forms, but typically, only one enantiomer is responsible for the desired physiological effect. The other form can have dangerous side-effects, as infamously occurred with the sedative thalidomide, discovered by the German company Grünenthal, which caused severe birth defects among children born in the late 1950s and early 1960s.

Since this crisis, drug developers have strived to create drugs containing only one enantiomer. However, it is possible that a single enantiomer can react with basic compounds in the water in the human body and flip its orientation.

In their study, published in Angewandte Chemie, the team set up experiments to simulate the conditions of the human body and then tested more than 40 drug compounds to monitor the rate at which they flipped. From these results, they produced a mathematical model that will enable drug developers to predict the rate of racemisation and avoid costly development of potentially-dangerous drug candidates.

“[Developers] can weed out compounds that are highly likely to be unsuccessful at a far earlier stage, plus our tool allows them to think about ways to change the chemical structure,” Niek Buurma, lead author of the study from Cardiff University, told The Chemical Engineer.

Questioned about the tool’s commercial readiness, Buurma noted: “It is being implemented at AstraZeneca”.