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450ANALESRANFwww.analesranf.comDeuterium in PharmacologySantiago Cu%u00e9llar Rodr%u00edguezAn. R. Acad. Farm.Vol. 90. n%u00ba4 (2024) %u00b7 pp. 449-470ABSTRACTIsomers and isosteres play a key role in the molecular modelling and optimisationof drugs. A special type of isosteres are isotopologues, chemical species thatcontain a different isotope of at least one of the atoms of the referencemolecule. The most obvious example is the substitution of one or moreconventional hydrogen atoms or protium (1H) by deuterium (D or 2H), which is astable (non-radioactive) isotope. Both isotopes are very similar in terms ofphysicochemical properties, although the carbon-deuterium (C-D) bond is morestable 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 reactionrate, when the substitution occurs in a C-H bond involved in some relevant aspectof the interaction with biological receptors or metabolising enzymes. The kineticisotope effect of deuterium %u2013 deuteration (substitution of one or more H atomsby D) %u2013 can affect the pharmacokinetics of a good number of drugs that aremetabolized by pathways that involve the cleavage of the C-H bond (C-D, in thiscase), which could improve some limitations of non-deuterated (parent) drugs,optimizing the pharmacokinetic properties to lead to a lower or less frequentdosage and, what is even more important, limit or decrease the formation ofnon-selective metabolites of the drug and, thus, improve its drug selectivity ortoxicological profile. In addition, it can be a tool to modulate and optimize theproperties of some drugs by inducing specific stereoelectronic effects.To date, 6 deuterated drugs have been approved, although the number of drugsin advanced clinical research phases is large and rapidly increasing, especially inthe areas of cancer, neurology and psychiatry, as well as in autoimmune,metabolic and infectious pathologies. All this offers a hopeful perspective in thedevelopment of new, more effective, safe and predictable drugs. However,sometimes the impact of deuteration may not be as expected due to unforeseenmultidirectional metabolic changes, reduced efficacy and interspecies variabilitythat jeopardizes the predictability of preclinical tests. Most majorpharmaceutical companies have taken the de novo deuteration route, making itan integral part of molecular design procedures for new drugs to optimize notonly pharmacokinetic conditions but also other aspects such as release andabsorption, as well as stabilization of certain pure stereoisomers of drugs toincrease their activity and mechanistic understanding while preventinginterconversion to potentially toxic or pharmacologically divergentstereoisomers.In conclusion, deuteration is an interesting and constantly evolving approach withmultiple and sometimes unforeseen applications.KEYWORDS Molecular designisotopologydeuteriumdeuterationpharmacologypharmacokineticsLa mayor%u00eda de las grandes compa%u00f1%u00edas farmac%u00e9uticas ha tomado el camino de ladeuteraci%u00f3n de novo, convirti%u00e9ndola en una parte integral de los procedimientosde dise%u00f1o molecular de nuevos f%u00e1rmacos para optimizar no solo las condicionesfarmacocin%u00e9ticas sino tambi%u00e9n otros aspectos como la liberaci%u00f3n y absorci%u00f3n, as%u00edcomo la estabilizaci%u00f3n de ciertos estereosi%u00f3meros puros de f%u00e1rmacos paraincrementar su actividad y el conocimiento mecan%u00edstico y, al mismo tiempo,impedir la interconversi%u00f3n a estereois%u00f3meros potencialmente t%u00f3xicos o divergentesfarmacol%u00f3gicamente.En conclusi%u00f3n, la deuteraci%u00f3n es un interesante enfoque en constante evoluci%u00f3ncon m%u00faltiples y, en ocasiones, imprevistas aplicaciones.