Deuterium in Pharmacology

Isomers and isosteres play a key role in the molecular modelling and optimisation of drugs. A special type of isosteres are isotopologues, chemical species that contain a different isotope of at least one of the atoms of the reference molecule. The most obvious example is the substitution of one or more conventional hydrogen atoms or protium (¹H) by deuterium (D or ²H), which is a stable (non-radioactive) isotope. Both isotopes are very similar in terms of physicochemical properties, although the carbon-deuterium (C-D) bond is more stable than the carbon-hydrogen (C-H) bond and its cleavage occurs more slowly, so the isotopological substitution of D by H could significantly modify the reaction rate, when the substitution occurs in a C-H bond involved in some relevant aspect of the interaction with biological receptors or metabolising enzymes. The kinetic isotope effect of deuterium – deuteration (substitution of one or more H atoms by D) – can affect the pharmacokinetics of a good number of drugs that are metabolized by pathways that involve the cleavage of the C-H bond (C-D, in this case), which could improve some limitations of non-deuterated (parent) drugs, optimizing the pharmacokinetic properties to lead to a lower or less frequent dosage and, what is even more important, limit or decrease the formation of non-selective metabolites of the drug and, thus, improve its drug selectivity or toxicological profile. In addition, it can be a tool to modulate and optimize the properties of some drugs by inducing specific stereoelectronic effects. To date, 6 deuterated drugs have been approved, although the number of drugs in advanced clinical research phases is large and rapidly increasing, especially in the areas of cancer, neurology and psychiatry, as well as in autoimmune, metabolic and infectious pathologies. All this offers a hopeful perspective in the development of new, more effective, safe and predictable drugs. However, sometimes the impact of deuteration may not be as expected due to unforeseen multidirectional metabolic changes, reduced efficacy and interspecies variability that jeopardizes the predictability of preclinical tests. Most major pharmaceutical companies have taken the de novo deuteration route, making it an integral part of molecular design procedures for new drugs to optimize not only pharmacokinetic conditions but also other aspects such as release and absorption, as well as stabilization of certain pure stereoisomers of drugs to increase their activity and mechanistic understanding while preventing interconversion to potentially toxic or pharmacologically divergent stereoisomers. In conclusion, deuteration is an interesting and constantly evolving approach with multiple and sometimes unforeseen applications. Keywords: Molecular design; Isotopology; Deuterium; Deuteration; Pharmacology; Pharmacokinetics