In spite of the widely used deuterated compounds in biomedical, deuterated-containing compounds have rarely been clinically explored in the context of creating new therapeutic agents. Recently, there has been a resurgence of interest in the application of deuterium in medicinal discovery and companies have started to pay big sums for heavy-hydrogen drugs. In 2017, the US Food and Drug Administration cleared the first deuterated drug, Austedo (deutetrabenazine), from Teva of Petach Tikva, Israel, for the treatment of Huntington's disease-related movement disorders. And today, many deuterated drugs have entered the clinical stage, as shown in Table 1 . Of course, the development of deuterated drugs is inseparable from the participation of deuterated compounds. Deuterated compounds play a huge role in the development of deuterated drugs as drug precursors, intermediates, raw materials, etc. It is an essential part of the development of deuterated drugs.
Table 1. Selected deuterated drugs in clinical development.
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Advantages of deuterated drug
There are several advantages of deuterated drugs. First of all, deuterated drugs swap hydrogen atoms for deuterium at selected locations in the molecular structure. With that chemical change, modified drugs can resist metabolic degradation and remain active for longer in the body than the parent compound. Secondly, the deuterium is introduced at strategic sites in the molecular structure, resulting in compounds with deuterium–carbon bonds that are up to ten times stronger than the hydrogen–carbon bonds, which will protect deuterated drugs from enzymatic degradation in the liver, increasing the drug's half-life. And then, it is possible to use deuterium to stabilize enantiomers of a drug into a desired orientation, avoiding the enantiomer accidents like Thalidomide incident.
Application in practice
Currently, the drug VX-984, involving a deuteration that slows this aldehyde oxidases metabolism, is in development. Koniarczyk et. al. developed a method for deuterating pyridines and diazines by first transforming them into phosphonium salts and then reacting these salts with D2O and K2CO3. Today, around 50% of the top-selling pharmaceuticals contain N-alkylamine groups. Recently, Chang et. al. developed an efficient deuteration reaction of β-amino C−H bonds used in various N-alkylamine-based pharmaceutical compounds. The reaction adopts acetone-d6 as a deuterium source and B(C6F5)3 as a catalyst. The reaction begins with the action of B(C6F5)3 and N-alkylamine, converting a drug molecule into the corresponding enamine. The catalysts also promote the deuteration of acetone-d6 to afford a deuterated ammonium ion. Ensuing deuteration of the enamine then leads to the formation of β-deuterated bioactive amines with up to 99% deuterium incorporation .
Fig. 1 The mechanism of deuteration reaction of β-amino C−H bonds with acetone-d6 as a deuterium source and B(C6F5)3 as a catalyst.
What can we do?
Alfa Chemistry has been committed to the development of medicine, and we manufacture and supply a range of deuterated precursors, deuterated intermediates and deuterated raw materials for deuterated drug development. And we also provide our customers with high-quality stable isotope-labeled compounds design and customization services. No matter what design ideas you have, we will implement them together with you. Please contact us immediately to order or cooperate in research and development with high quality and reasonable price.
- Mullard, A. FDA approves first deuterated drug [N]. Nat. Rev. Drug. Discov, 2017, 16, 305: 493-494.
- Chang, Y.; et al. Catalytic deuterium incorporation within metabolically stable β-amino C–H bonds of drug molecules[J]. J. Am. Chem. Soc. 2019, 141 (37), 14570–14575.
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