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The famous pharmacology James Black once said that the best way to develop a new drug is to start with an old medicine. Roger Tung has a deep understanding of this sentence.
Tung has worked in Mercedes and Vertex for decades, and has seen too many cases of drug development failure. There are many reasons for the failure of drug research and development. From the point of view of the drug target, if the drug target itself does not have a drug resistance, even if the potential preclinical data are obtained, the data can not be converted to the benefit of patients in the bed test due to the limitations of the prediction of the model in vitro and animal models.
On the other hand, even if the drug target does not exist, the pharmacokinetic properties of the drug or the defects of the drug may also lead to the failure of drug development.
Although the probability of new drug development is very low, failure is the norm for new drug research and development, but after Tung left Vertex, he has been thinking about how to better avoid the risk of new drug research and development failure. At the time, Tung thought that deuterated drugs seemed to be a good choice, which could optimize existing drugs and improve the pharmacokinetic properties of drugs by deuterium generation.
As the efficacy of existing drugs has been clinically proven, deuterated drugs only need to prove that deuterium drugs can be listed on the market by comparing the existing drugs to the existing drugs, as well as the patent protection that can avoid the existing drugs. That seems much simpler than developing a new drug from scratch. So Tung set up Concert Pharmaceuticals in 2006, focusing on the research of deuterium drugs.
In fact, deuterium is not a new concept, and at the beginning of the Concert, many pharmaceutical companies and laboratories in academic institutions have carried out a number of deuterium research and development projects.

Rebirth of old medicine

The deuterium atom is only one neutron more than the hydrogen atom, which does not have any effect on the chemical structure of the compound, but the reactivity of hydrogen is changed after replacing deuterium, because the C-D bond is more difficult to break than the C-H bond.
Drug chemists have been very interested in this change for a long time, because a lot of drug metabolism starts from the step of C-H bond breakage. If a pharmaceutical company can replace the hydrogen in the specific part of the drug molecule to deuterium, it may have an effect on the metabolic process of the drug, thereby slowing down the metabolic rate of the drug, prolonging the half-life of the drug or inhibiting the production of toxic metabolites.
It also has an important advantage over other structural modification methods: deuterium usually does not change the biophysical properties of the drug, affects the molecular character, size, or the ability to combine with the target.
In the 70s and 80s of last century, Mercedes conducted a research and development of a deuterium antibiotic fludalanine. Fludalanine is the first deuterium compound to conduct in-depth clinical studies. Drug chemists hope to inhibit the formation of toxic metabolites through deuterium, but eventually the project ended in failure. Because of the detection of these toxic metabolites in the blood of patients with bronchitis in the two phase of clinical studies, merschon was forced to stop the project.
In the next few decades, the development of deuterium drugs has begun to rise and fall, and some pharmaceutical companies, including Concert, have focused on Deuterium drug research and development, and these pharmaceutical companies have also succeeded in promoting clinical research with some candidate drugs. Last year, FDA approved the first ever deuterium drug listing in history.
The Austedo of Teva is deuterated bububenzazine. The detailed mechanism of budiazine is still unclear, but it is generally believed that the drug can inhibit the uptake and storage of monoamine neurotransmitters such as dopamine, norepinephrine and serotonin by reducing the vesicle of monoamine transporter 2 (VMAT2), so as to treat the involuntary transport associated with Huntington’s chorea. Move.
For decades, butazine has been the mainstay of Huntington’s disease. But the half-life of the drug is very short. Patients need to take the drug two to three times a day. And with the decrease of blood concentration, withdrawal symptoms will occur.

Therefore, drug chemists hope to slow down the metabolism of butadiazine by deuterium, and replace the six hydrogen atoms of the two methoxyl groups in the budiazine structure into six deuterium atoms. These methoxyl groups are the key metabolic sites for active drugs to metabolize non active compounds. After deuterium, the metabolic process can be slowed down significantly, which reduces the dosage of Austedo, decreases the frequency of drug use and inhibits the emergence of withdrawal reaction.

Austedo was originally developed by AuspexPharmaceuticals, and in 2015, Teva bought the company at a price of US $3 billion 500 million. A few months later, Teva submitted a listing application for Austedo to FDA.
But Teva used the safety data of butazine in its application. Although Austedo is identical to the metabolites of butazine, FDA still requires Teva to submit quantitative data on Austedo metabolites. Despite some twists and turns, FDA finally approved Austedo in early 2017.
Perhaps the clinical progress of a series of deuterium drugs such as Austedo has made pharmaceutical companies see the hope that the pharmaceutical companies over the past two years have a high degree of concern for deuterium drugs. Last March, Concert sold its company’s CTP-656 at $160 million in cash and ninety million mileage gold to Vertex.
CTP-656 is the deuterium version of the Kato (ivacaftor). The half-life of CTP-656 is 15 hours, while the half-life of the deuterium plate is 12 hours, and the drug’s frequency can be reduced from two times a day to one day. Moreover, unlike CTP-656, there is no need for a fatty diet to enhance the absorption of drugs.
In addition to CTP-656, Concert has conducted another famous research on Deuterium drugs. Dextromethorphan is an antitussive drug discovered in the 40s of last century. It can act on many receptors in the brain. However, dextromethorphan is metabolized rapidly, so the pharmaceutical industry has also done a lot of research on slowing down the metabolic process of dextromethorphan.
In 2010, Avanir’s Nuedexta received FDA approval to treat a mental disorder associated with brain damage: pseudobulo bulbar affect (pseudo – bulbar affect). Nuedexta is a combination of drugs including dextromethorphan and quinidine. Quinidine can slow down the metabolism of dextromethorphan, so that drugs can stay in the body circulation for a longer time.

But quinidine has some side effects, so Concert scientists have tried to deuterium modification to the structure of dextromethorphan and replace the hydrogen atoms of Byscharfenka Ki and methylamino as deuterium. These two substituents are also the key points for the metabolism of dextromethorphan. This conversion can prolong its half-life and reduce the quinidine dosage in AVP-786 by half.
At the time of Concert’s preclinical study of the deuterium compound, the company Avanir, which developed Nuedexta, worked with Concert to carry out AVP-786 research, hoping to replace dextromethorphan in Nuedexta as deuterium dextromethorphan and get a more stable drug with quinidine. In 2015, Avanir was bought by Otsuka at a price of US $3 billion 500 million. At present, AVP-786 is in phase III clinical research.
Although deuterium can optimize the nature of some of the existing drugs, deuterium studies are not limited to the listed old drugs, and many pharmaceutical companies have begun to use deuterium to optimize the discovery of the precursor compounds in the process of new drug development. Vertex’s drug VX-984 is one example.
Vertex scientists have obtained a precursor of a DNA dependent protein kinase (DNA-PK) inhibitor, but later studies have found that the compound is metabolized very quickly, and one of the pyrimidine rings in the compound is easily metabolized by aldehyde oxidase.
They have tried many methods to optimize their metabolism, such as adding substituents to the pyrimidine ring, modifying the electrophilic substitution reaction activity of the pyrimidine ring, or replacing the two hydrogen atoms involved in the metabolic process.
Although all of the compounds obtained can not be metabolizing aldehyde oxidase, other properties of the compound can be changed together, and the compounds that have the same activity as those of the pilot compound can not be obtained. Eventually, they decided to replace two hydrogen atoms involved in the metabolic process site to deuterium and get the compound VX-984. Deuterium also slowed down the metabolism of aldehyde oxidase and reduced the metabolic rate of the compound to a reasonable level.

In addition to prolonging the half-life and inhibiting the generation of toxic metabolites, deuterium still has an interesting use to prevent drug isomerization inactivation.
Most researchers should be familiar with the story of thalidomide. Thalidomide is a mixture of two enantiomers, one of the enantiomers that can relieve morning sickness in pregnant women and the other to cause severe congenital malformation.
However, thalidomide, which only takes the R configuration, can not solve the side effects of thalidomide, because the chiral center of thalidomide is adjacent to the carbonyl group. Therefore, the chiral center is easily racemed in the human body, so that the single configuration compound can re form a raceme with R and S configurations. That is to say, even with the drugs of R configuration, the drug will still produce an enantiomer that can cause harm in the body.
However, if the hydrogen in the chiral center is replaced by deuterium, it will probably slow down the racemization process. DeuteRx is a company focused on deuterization to inhibit racemization. The company is doing research on the deuterated version of thalidomide analogues.
Another compound DRX-065 of the company is the R configuration of pioglitazone. Pioglitazone is a commonly used drug for diabetes treatment, but it can sometimes cause weight gain or edema. The researchers suspect that only S pioglitazone can cause these side effects. At present, DRX-065 is in the stage of clinical I.


At present, there are a lot of deuterium drugs in clinical research. In the field of deuterium drugs, such as zawless biology and Chengdu sea invasive companies are also distributed in the field of deuterium drugs. For example, Dorgan dnnfitni has entered the III phase clinical study, and Jack Tanei has also entered II phase clinical.
However, deuterium is only a means for chemists to optimize the properties of compounds from the perspective of drug based research. In a particular case, the application of deuterium is very limited and does not apply to all compounds.
Although deuterated drugs based on old drugs are less risky than developing a new drug, this does not mean that there is no risk of failure in these drugs.
First, although deuterium generally does not affect the activity of the original drug, in a few cases, the deuterium may cause a slight change in the hydrophobicity or acidity and alkalinity of the compound, which leads to the changes in the biological activity of the drug, which is difficult to predict at present.
Secondly, it is also unknown whether the half life of drugs can be prolonged after deuterium and the generation of toxic metabolites is inhibited. Moreover, even after deuterium can alter the metabolism process of the drug, it does not mean that the difference of metabolism will be able to turn into patients’ benefit.
Moreover, there are some pharmaceutical companies that do deuterium drugs just to avoid the patent of existing drugs. If the deuterium compound is designed only from the angle of patent protection and the deuterium subrogation point is selected, the result may not only be unable to optimize the properties of the existing drug, but will reduce the quality of the drug and make the me worse.
The development of deuterium drugs is not as simple as many people think. The value of deuterium drugs is to overcome some defects of existing compounds, such as short half-life, toxic metabolites, and easy racemization. It is not easy to find a reasonable way to solve these problems based on Deuterium generation. Even if there is a relatively reasonable design of deuterium drug molecules, there may be many obstacles to the synthesis of deuterium compounds.
Most importantly, even if it is possible to complete the synthesis of deuterium compounds, it is also a big problem to break through patent protection.
Pharmaceutical companies have not recognized the necessity of patent protection for deuterium compounds for a long time, and even if the claims in many patents contain deuterated compound structures, these compounds have not been truly synthesized, obtained compound spectra, deuterium subrogation points, and test their birth. Physical activity.

This also makes the patent of existing drugs have great room for excavation. However, as pharmaceutical companies’ awareness of patent protection for deuterium compounds is enhanced, other pharmaceutical companies will also be more difficult to break through the patent protection of these companies.
At present, many companies engaged in the development of deuterium drugs are actually using the strategy similar to that used by Sepracor in 80s of last century.
A few decades ago, patents applied by pharmaceutical companies rarely contained information about drug isomers. As with thalidomide in the previous article, there are sometimes great differences in the biological activity of various isomers that exist in many chiral centers.
And Sepracor’s business model is based on the search for a single configuration drug that has been listed as a proactive agent. Although this model is enough to support the growth of Sepracor within a lot of years, pharmaceutical companies are soon beginning to clarify the information of the compound isomers in the patent.
Perhaps in the near future, this method of deuterium will gradually lose the function of its breakthrough compound patent and return to the essence of service research.

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