New iridium-catalysed methods for the direct preparation of isotopically-labelled compounds for metabolism studies

Within the pharmaceutical industry, approximately 60% of all novel molecular entities fail in pre-clinical trials. This alarming rate of attrition results in increased costs and delays in bringing medicines into the clinic. One strategy to address this issue is to assess the pharmacokinetic properties of candidate molecules at an earlier stage in the drug discovery process. More specifically, the early application of adsorption, distribution, metabolism, excretion, and toxicology (ADMET) studies is key to addressing the failure rates within the drug discovery process and, in turn, clinical trials. Within ADMET studies, isotopically-labelled compounds are extensively applied in the detection and quantification of drug-related metabolites. In terms of the preparation of labelled molecules, hydrogen isotope exchange (HIE) stands out due to its versatility and the practicality of late-stage isotope introduction. Foremost amongst this approach is the use of iridium-catalysed directed HIE, where a specific group in the molecule directs the catalyst to introduce the required adjacent isotopic label.