Drug design is a very long and expensive process and sometimes unexpected results such as poor stability, toxicity of a metabolite or some drug-drug interaction of the drug candidate can be encountered. To prevent or at least to limit the formation of unwanted metabolites, a medicinal chemist selects the problematic parts of the molecule and applies specific substitution using bioisosteric replacement to improve the structure. The most common and well described replacement for hydrogen atom is fluorine. It is estimated that around 20% of all commercialized pharmaceuticals contain fluorine. However, introduction of fluorine into a molecule can influence its conformation, pKa, membrane permeability, metabolic pathways and its pharmacokinetic properties.
Recently, a number of studies have been performed on selective replacement of hydrogen (protium) with deuterium, naturally occurring and stable isotope of hydrogen. The increased C-D bond strength (6-10-fold) usually results in increased metabolic stability of the molecule and extended metabolic half-life of the drug. [1]
We would like to present here a few published results where incorporation of deuterium really made a difference, to the point that some of the compounds are currently in clinical trials.
1. d2-Paroxetine (CTP-347)
Example of increasing the safety by decreasing drug-drug interactions.
Paroxetine (commonly known as Paxil) is a selective serotonin reuptake inhibitor (SSRI) and it is currently used for anxiety disorders, major depression and posttraumatic stress disorder (PTSD). It was approved by the FDA in 1900s and marketed by SmithKline Beecham Pharmaceuticals. [2] It was also the first non-hormonal treatment for hot flashes associated with menopause, approved by FDA in 2013 as Brisdelle, which is a mesylate form of paroxetine.
Despite its healing effects, patients taking specific medications cannot take it because the CYP2D6 metabolizes the methylenedioxy part of the paroxetine molecule to a carbene which forms a covalent complex known as a metabolic-intermediate complex (MIC) with the cytochrome P450-Fe(II) form of the enzyme and inhibits its activity in a quasi-irreversible fashion. (Scheme 1) [3]
CYP2D6 is responsible for metabolizing around 25% of all drugs and inactivating it can cause dangerous increase in the blood level of the other drugs that patient is taking.
In 2015 Concert Pharmaceuticals decided to use precision deuteration technique on Paroxetine to reduce these drug-drug interactions caused by first-pass metabolism of the drug. The IC50 levels for serotonin and dopamine reuptake inhibition were very similar for deuterated and protium version of Paroxetine. This was the proof that deuterium substitution has no significant effect on the pharmacological activity of the drug. The scientists also tested these drugs for stability against human liver microsome (HLM). It turned out that CTP-347 was metabolized faster than the protio-drug probably as a result of significant decrease in inactivation of CYP2D6. Perhaps it’s because the changes in the path of metabolism from pathway A to pathway B, which favors the ring opening route, lead to innocuous metabolite and avoid formation of carbene (Scheme 1). This deuteration was the first clinical demonstration where the deuterium substitution could be utilized to ameliorate drug-drug interactions in humans.
2. d6-Dextromethorphan (AVP-786)
Example of increasing safety by bimodal slowing metabolism
Dextromethorphan was developed by Hoffman-La Roche in 1954 as an antitussive agent. Nowadays it is a common ingredient of more than 125 commercial cough and cold remedies. [4] Dextromethorphan suppresses the cough reflex by direct action on the cough center in the medulla of the brain.
In vivo, dextromethorphan (DM) undergoes first-pass metabolism in the liver by two possible pathways as shown on Scheme 2. [5]
In Nuedexta, a drug containing a fixed dose of dextromethorphan and quinidine, the latter is used to inhibit CYP2D6 and slow the formation of dextrorphan (DX, NMDA receptor antagonist responsible for psychoactive effects), while enhancing exposure to the parent drug. However, quinidine can cause some unwanted cardiac side effects. [7,8] Thus Scientists at Concert Pharmaceuticals used selective deuteration as a tool to reduce this first-pass liver metabolism. They partnered with Avanir Pharmaceutical and developed AVP-786, a deuterated version of Nuedexta, and more specifically, a deuterated version of dextromethorphan, which contains -CD3 moieties in crucial parts of the molecule that undergo O- and N-demethylation. By making this simple deuterium-switch, the amount of quinidine, previously required to inhibit CYP2D6 for nondeuterated DM, could be cut by more than half for deuterated version of this drug. The deuterated dextromethorphan has similar pharmacological profile as dextromethorphan but due to the deuterium isotope effect it is less susceptible to CYP2D6 catalyzed metabolism. [5] In October 2017, AVP-786 reached Phase III clinical trials for the treatment of agitation in people with dementia of the Alzheimer’s type and the estimated time to complete this study is in June 2021. It is also in Phase II for the treatment of brain injuries, impulse control disorders and neurodegenerative disorders. [6] The unquestionable advantage is that as a new compound, AVP-786 will also have longer patent protection, which expires in 2030 in the USA and in 2028 in Europe in comparison to 2023 in both regions for Nuedexta.
3. d9-Ivacaftor (CTP-656)
Example of decreasing dosing frequency
Originally, Ivacaftor (brand name Kalydeco) was developed by Vertex Pharmaceuticals and was approved by FDA in 2012 as the first drug to treat an underlying cause of cystic fibrosis (CF) rather than the symptoms. Currently it is used in monotherapy as the product Kalydeco, and as a fixed-dose combination with lumacaftor under the brand name Orkambi.
As shown on Scheme 3, Ivacaftor is metabolized in the liver by CYP3A (CYP3A4 and CYP3A5) enzymes by oxidation of one methyl moiety of its one t-butyl groups to primary alcohol: hydroxymethyl-ivacaftor (M1), and partially further oxidized to carboxylic acid, Ivacaftor-carboxylate (M6). [7] In comparison with the protio compound, these two metabolites are less efficacious in enhancing functional response in vitro.
The scientists from Concert Pharmaceutical decided to apply the deuterium substitution in the tert-butyl group, so crucial for metabolism of this drug and developed a deuterated analog of Ivacaftor.
In vivo, deuteration of the important t-butyl group leads to a ≥ 3-fold increase in exposure to CTP-656 in comparison to Ivacaftor and an increase in half-life, whereas exposure to the deuterated M1 and M6 metabolites showed pharmacology equivalent to that of the corresponding protio metabolites. The deuterium isotope effects for d9‑Ivacaftor metabolism (DV= 3.8, DV/K=2.2) were notably large for a CYP 450-mediated oxidation. In Phase 1 crossover study comparing deuterated Ivacaftor and the parent drug, the CTP-656 showed reduced clearance, longer half-life, substantially increased exposure and greater plasma levels at 24h. All these factors suggest that this deuterated analog may be dosed once daily, in comparison to the parent drug, which was dosed twice a day. The study also indicated that it doesn’t need to be taken with a fatty meal, as Ivacaftor does for maximum efficacy. [8]
4. d1-Thalidomide
Example of reduction of epimerization and toxicity
Many of us are familiar with the thalidomide case. Thalidomide as racemate was marketed in 1956 by Chemie Grünenthal, first as an anti-flu, then in 1957, as a hypnotic drug in Europe. It was available without prescription. Back then, Thalidomide appeared as a promising alternative to barbiturates that were then used as sedatives, because it seemed to be safe and even after overdose it would cause deep sleep in comparison to barbiturates, which could cause death if taken in excessive quantity. [9] The drug was prescribed to many pregnant women in order to relieve pregnancy nausea. It was later found that thalidomide caused irreversible damages to the fetus and thousands of children were born with severe congenital malformations. Many of them did not survive more than a few days after they were born. Later studies demonstrated that only the (R)- enantiomer is responsible for sedative effects, while (S)- thalidomide is teratogenic. Scientists tried to use pure (R)-thalidomide. However, in vivo tests showed that this drug undergoes rapid chiral inversion in humans so even if single enantiomer is applied, the second, harmful, enantiomer is also formed in the body as shown on Scheme 4.
Since then, many analogues of Thalidomide have been synthesized and tested, among them Avadomide (CC-122) developed by Celgene Corporations, which is pleiotropic pathway modulator with a broad range of activity, e.g. anty-inflammatory and teratogenic activity. This drug candidate is currently in Phase 2 clinical trials.
Similar to thalidomide, C-3 hydrogen is prone to racemization in vivo. In 2015 to avoid this, scientists from DeuteRx, keeping in mind that the C-D bond is stronger than C-H, incorporated the strategy called deuterium-enabled chiral switching (DECS). They prepared both enantiomers of deuterium analog of CC-122, with deuterium in C-3 position of the glutarimide moiety to explore the possibility of developing a single enantiomer drug for the treatment of multiple myeloma. They run biological studies to measure the difference between these two enantiomers. The inflammatory activity was tested by measuring the ability to inhibit TNF-α production. It turned out that the levorotatory isomer is 20-fold more potent than the dextrorotatory and that deuterium incorporation stabilizes the configuration of the chiral center. [10]
5. Deutetrabenazine (Austedo)
Example of PK improvement. First deuterated drug approved by FDA
Despite desirable properties of deuterium, many drug candidates didn’t even reach Phase III study. The breakthrough came in 2017 when the first deuterated drug approved by FDA, deutetrabenazine with brand name Austedo (SD-809), appeared. Deutetrabenazine is a deuterated form of tetrabenazine (Xenazine), the drug which has been known since the early 1950s but gained FDA approval in 2008 and became the first treatment for Huntington’s disease in the US. Deutetrabenazine, which has the same indications as the parent drug, was approved via a hybrid regulatory pathway (505(b)(2) ) that allows the applicant to avoid unnecessary duplication of studies by following a development process that enabled referencing of certain nonclinical and safety findings previously reported for the parent compound. Moreover, Teva Pharmaceuticals received FDA approval to submit deutetrabenazine as a new chemical entity. It also received five years of orphan drug exclusivity for the treatment of chorea associated with Huntington’s disease. [11] This great news encouraged scientists from pharmaceutical industry to perform more research into the application of deuterated analogs of drugs that are already on the market.
The substitution of deuterium for hydrogen at methoxy groups in the tetrabenazine molecule slows rate of drug metabolism (Scheme 6), thus prolonging plasma half-life (twice) and reducing fluctuations of drug levels in the plasma without altering protein-binding interactions. [12] This allows less frequent and lower drug dosing (from 3 to 2 per day), which results in a more favorable side effect profile.
- Katarzyna Ciepiela
Scientist III
Selvita S.A.
Reference:
[1] Schmidt, C., Nature Biotechnology, 2017, 35, 493-494
[2] Tulloch, I.F., Johnson, A.M., J Clin Psychiatry,1992, 53, 7-12
[3] Uttamsingh V., et al., J. Pharmacol. Exp. Ther, 2015, 354, 43-54
[4] Bem JL., Peck R., Drug Safety, 1992, 7, 190-199
[5] Garay, R. P. and G.T. Grossberg, Expert Opinion on Investigational Drugs, 2017, 26, 1, 121-132
[6] ClinicalTrials.gov Identifier: NCT03393520
[7] Robertson SM, et al., J Clin Pharmacol., 2015, 55, 56–62
[8] Harbeson, S., et al., Journal of Pharmacology and experimental therapeutics, 2017, 362, 2, 359-367
[9] WO 2017/192905 Al
[10] Pirali, T., et al., J. Med. Chem., 2019, 62, 5276-5297
[11] Yero, T.; Rey, J. A., P. & T , 2008, 33(12), 690–694
[12] Huntington Study Group, Frank S. et al., JAMA, 2016, 316, 40-50