Deuterated Drugs Research Progress

What are Deuterated Drugs?

Deuterated drugs are medications obtained by substituting hydrogen atoms at specific positions on drug molecules with deuterium atoms. The most widely used application involves replacing carbon-hydrogen (C-H) bonds with carbon-deuterium (C-D) bonds. Through this substitution, the pharmacokinetics and toxicity of the drugs can be improved. In April 2017, the United States Food and Drug Administration (FDA) approved the world’s first deuterated drug, Deuterabenazine (sold as Austedo by Auspex Pharmaceuticals), for commercialization. It is used for the treatment of the rare autosomal dominant genetic disorder, Huntington’s disease. In 2022, the FDA approved another novel deuterated drug, Deucravacitinib, which finds extensive application in treating various autoimmune diseases, including primary Sjögren’s syndrome, rheumatoid arthritis, and psoriasis, among others.

Deuterium Kinetic Isotope Effect (DKIE)

Medicinal chemists employ various methods to enhance the structure of candidate compounds, aiming to improve their efficacy and safety. Among these methods, deuterium substitution for hydrogen can be considered the subtlest chemical alteration, yet it can have profound impacts on the properties of candidate compounds. Initially, deuterated drugs were primarily thought to enhance the metabolic stability of candidate compounds. However, as research has progressed, the effects of this modification have been found to extend far beyond simple pharmacokinetic (PK) improvements, significantly influencing the efficacy and safety of the drugs.

Hydrogen is the most abundant element in the universe and exists in three isotopes: hydrogen-1 (¹H, referred to as H, with one proton and one electron, abundance 99.9844%), deuterium (²H, referred to as D, with one neutron, abundance 0.0156%), and tritium (³H, referred to as T, with two neutrons, trace amounts). Tritium is a radioactive isotope with a relatively long half-life (t_1/2), while deuterium is more stable. With the emergence of ultra-sensitive mass spectrometry techniques, deuterium (D) has found widespread applications in the field of biomedicine.

Deuterium (D) is formed through nuclear fusion during the period of the Big Bang. In 1932, Harold Urey first discovered and named it. H and D possess highly similar physicochemical properties. D has a smaller molar volume (0.140 cm³/mol⁻¹/atom), lower lipophilicity (ΔlogP_oct-0.006), and shorter C-D bond length compared to the C-H bond. The molar mass of D is twice that of H, resulting in a lower vibrational frequency and ground state energy of the C-D bond, leading to an increase in dissociation activation energy. Consequently, the C-D bond is more stable than the C-H bond (with a difference of 1.2-1.5 kcal/mol), exhibiting slower dissociation rates. This disparity can be quantified through Deuterium Kinetic Isotope Effects (DKIE), expressed as the ratio of rate constants (k_H/k_D). Higher DKIE values correspond to slower C-D bond cleavage rates compared to C-H values. When comparing C-H cleavage rates to C-D cleavage rates, primary isotope effects emerge, with values typically ranging from 1 to 5. In specific cases, DKIEs can be <1 or >5, with a theoretical upper limit of 9. However, taking into account the cumulative effect of DKIEs, isotope substitution from distal parts of the molecule (i.e., distal DKIE) impacts cleavage. This effect can lead to significant DKIE values, slowing down the chemical bond cleavage rate, and exerting profound influences on enzyme-catalyzed processes. Thus, deuterium substitution can be utilized from different perspectives to enhance drug properties.

Benefits of Deuterated Drugs

More than half of the marketed drugs are metabolized by enzymes from the cytochrome P450 (CYP) family. However, oxidative metabolism may carry risks associated with metabolite formation: generating unstable, reactive, non-selective, and toxic intermediates and/or metabolites; genetic polymorphism leading to differences in the types or proportions of metabolites among patients; and saturation, induction, or inhibition of isoforms, resulting in potential drug-drug interactions. Therefore, the strategy of replacing H with D based on DKIE is employed in drug development to mitigate the inherent drawbacks of CYP-mediated metabolism and its alterations. Importantly, in order to observe significant DKIE and the impact of D on oxidation rates, the catalytic cycle must involve C-D bond cleavage. Moreover, the magnitude of DKIE depends on the metabolic pathway, enzymes involved, and specific substrates. Generally, O-dealkylation is the most sensitive reaction to deuterium substitution, followed by N-dealkylation of amides and oxidation of alkyl groups. Conversely, N-dealkylation of amines is the least sensitive transformation, and hydroxylation of aromatic rings is unaffected by H-to-D substitution.

The PK Advantage of Deuterated Drugs

Drug developers utilize deuterium substitution-induced changes in drug metabolism rate to optimize drugs mainly in the following aspects:

(1) Deuterium substitution-induced changes often result in reduced clearance, prolonged half-life, and increased systemic exposure of the drug.

(2) For drugs with significant first-pass effects, deuterium substitution can decrease their first-pass effect, thereby increasing oral bioavailability.

(3) Deuterium substitution can decrease the formation of specific metabolites, thereby improving the metabolic profile.

(4) Deuterium substitution at chiral centers in stereoisomers can reduce mutual interconversion between stereoisomers, thus stabilizing a single stereoisomer.

Reduced clearance and increased systemic exposure: CTP-656 is the deuterated form of the investigational drug Ivacaftor (brand name: Kalydeco™). Its intended use is the same as Ivacaftor, which is indicated for the treatment of cystic fibrosis caused by specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In vitro experiments demonstrate that CTP-656’s pharmacological activity is similar to Ivacaftor, but deuterium substitution significantly slows down its metabolic rate (primarily the alkyl oxidation reactions catalyzed by CYP3A4 and CYP3A5). In animal experiments, at a dose of 10.0 mg·kg^-1, after oral administration of CTP-656 to rats, the Cmax, t_1/2, and AUC are 1.03, 1.26, and 1.09 times those of Ivacaftor, respectively. For dogs, after oral administration of CTP-656, the Cmax, t_1/2, and AUC are 1.54, 1.29, and 1.69 times those of Ivacaftor, respectively. Initial human trial results for CTP-656 show that, compared to historical data for Ivacaftor 25 mg, healthy subjects administered CTP-656 25 mg orally exhibit increasing trends in AUC, Cmax, and t_1/2.

Reduced first-pass effect and increased oral bioavailability: Atazanavir (brand name: Reyataz™) is an oral human immunodeficiency virus (HIV) protease inhibitor(PI), commonly used in combination with ritonavir to treat HIV-1 infection. Atazanavir has a strong hepatic first-pass effect, extensively metabolized by CYP3A4/CYP3A5, and exhibits low oral bioavailability (15% in rats; 36% in dogs). Ritonavir, being both an HIV PI and a strong CYP3A inhibitor, can act as a pharmacokinetic enhancer, improving the oral bioavailability of Atazanavir and enhancing its antiviral efficacy. However, ritonavir can cause adverse effects such as hyperlipidemia, hyperglycemia, and gastrointestinal intolerance. CTP-518 is the deuterated form of Atazanavir, and its researchers aim to develop an HIV PI that retains the antiviral activity of Atazanavir without the need for co-administration of ritonavir or other pharmacokinetic enhancers through deuterium substitution. In vitro experiments show that CTP-518 exhibits similar antiviral activity to Atazanavir, while increasing the half-life in human liver microsomes by 51%. In animal experiments, following intravenous administration in monkeys, CTP-518 shows a 52% increase in half-life compared to Atazanavir.

Reduced specific metabolites and improved metabolic profile: Paroxetine (brand name: Paxil™) is an antidepressant and a common inhibitor of CYP2D6. Its carbene-type metabolite, formed through CYP2D6 metabolism, can irreversibly bind to CYP2D6, leading to the inhibition of its activity and slowing down its own metabolism. CTP-347 is the deuterated form of Paroxetine, and in vitro experiments show similar pharmacological activity between the two, but with differing degrees of CYP2D6 inhibition. Initial human trial results indicate that healthy subjects administered CTP-347 10 mg, once daily, for 14 days exhibited lower exposure compared to the corresponding dose of Paroxetine (Day 1 AUC_0-t: 8.3 vs 17.8 ng·mL^-1·h; Day 14 AUC_0-t: 18.0 vs 248.1 ng·mL^-1·h). The accumulation factor was also lower (2.9 vs 13.9). Furthermore, when compared to historical data for the corresponding dose of Paroxetine, continuous administration of CTP-347 20 mg, once daily, had a lesser impact on the metabolism of a CYP2D6 model substrate (dextromethorphan). These results suggest that deuterium substitution reduces the carbene-type metabolite, weakening the inhibitory effect of the drug on CYP2D6, thus reducing its interaction with CYP2D6 substrates.

Progress in Deuterated Drugs Research

Opportunities and Challenges of Deuterated Drugs

While the use of D in drug discovery has many advantages, it also has some disadvantages.

The ability to enhance the resistance of molecules to bond cleavage without significantly altering their steric hindrance or electronic properties is the major advantage of deuterated drugs. The influence of deuterium atoms on the overall characteristics of drug absorption, distribution, metabolism, excretion, and toxicity (ADMET) extends beyond metabolism. Although the difference in lipophilicity between H and D is negligible, the presence of multiple deuterium atoms may lead to changes in plasma protein binding rates.

In deuterium labeling strategies, the introduction of deuterated methyl groups (CD3) is the most common and convenient approach. This strategy utilizes a cost-effective and low-cost deuterium source that can meet the demands of large-scale production. It offers high reaction yields, relative stability of CD3, and minimal deuterium loss. Moreover, CD3 can be introduced at the early or late stages of synthetic processes, enhancing the process flexibility. While the incorporation of CD3 methyl groups constrains the structural diversity of such deuterated drugs, the rapid advancements in transition metal-catalyzed C-C coupling reactions enable the direct coupling of CD3I with halogenated aromatic compounds, facilitating the introduction of CD3 onto aromatic rings. This advancement is expected to greatly propel the development of CD3-labeled drugs.

For the metal-catalyzed ¹H-D exchange strategy, position selectivity and deuteration rate are a challenge, which limits the application of this strategy. Weak-acid and weak-base catalysis is relatively mild and is a good strategy for deuteration of active protons. However, for the need of strong acid and base conditions, the tolerance of the substrate is also a challenge. Therefore, for structurally diverse drug molecules, the development of homogeneous selective ¹H-D exchange metal catalysts using D2O as the deuterium source will be an important research direction.

References

1. R, M, Di.; et al. Deuterium in Drug Discovery: Progress, Opportunities And Challenges. Nat Rev Drug Discov. 2023, 22(7): 562-584.