Author: Liubiggeneral
Derivatization optimization of natural products can not only improve the dynamics of the body by changing the physicochemical properties such as solubility and stability of the compound, but also improve its activity and selectivity as a drug and reduce human toxicity. The natural product as a precursor for semi-synthesis of drugs and a template for chemical synthesis of drugs provides a broad idea for drug design.
Dimethylbiguanide (metformin) is a derivative of natural products and a basic drug for the treatment of type 2 diabetes mellitus (T2DM). It has been derived from long-term research on herbal goatpea and natural product. explore. Since its listing in 1957, metformin has been used for more than 60 years as a first-line drug, and its various hypoglycemic effects have been continuously discovered and confirmed. As an economical, safe and effective classic drug, it has always been I have not left the vision of medical workers and scientists, and have received more and more attention.
➢ Discovery of terpenoids
In medieval Europe, the above-ground parts of goat beans have been used as herbs to relieve polyuria, which is one of the typical symptoms of diabetes, which is also used in animal husbandry for animal lactation. In the 17th century, British botanist and physician Nicholas Culpeper (1616-1654) proposed that goat beans have anti-diabetic effects, and his views have attracted the attention of the British medical community and spread widely. In the 19th century, goat beans were introduced to the United States as pasture, but they were quickly found to be very toxic to livestock and even fatal, so they were included in the Federal Noxious Weed List. Goat beans are also harmful to the human body. During this period, it was found that goat beans contain a large amount of terpenoids, which are small molecules with three N atoms and strong alkalinity. Through animal experiments, scientists have discovered that steroids have hypoglycemic effects. This result was published in 1918, but because of the strong toxicity of terpenoids, researchers began to turn their attention to another compound in goat beans, namely goats. Beanine.
In 1914, the French scientist Tanret first extracted the gooseine (Galegine) from the goat bean seeds and conducted a preliminary study on the alkaloid; in 1923, Barger and White of Edinburgh, England, determined the chemical structure of the goat's base; 1925 In the year, German scientists Späth and Spitzy completed the chemical synthesis of crotonine; in 1927, Tanret continued to carry out pharmacological studies on natto, and in experimental animals (rabbits and dogs), crotonine showed sustained hypoglycemic effect and Serious toxic reaction; in the same year, German scientists Müller and Reinwein published the results of human clinical trials of crotonine. Three subjects showed hypoglycemia after taking crotonine. The blood glucose level was weaker in patients with normal blood sugar, while the blood sugar level in diabetic patients was lower. The effect is more obvious. Since then, many scholars have studied and explored the safety of improving the drug use of crotonine, and some progress has been made. However, in general, the difference in the therapeutic effect of crotonine and the short duration of action have limited its clinical application in the treatment of diabetes.
During this period, scientists synthesized a number of anthraquinone derivatives in order to obtain safe and effective treatment for diabetes drugs. In 1926, Frank et al. reported the hypoglycemic activity of a biguanide, decane biguanide. In the same year, Schering of Germany introduced it to the market under the trade name Synthalin A. In order to reduce its toxicity, Schering's other product, dodecane bismuth, was quickly introduced. The trade name is Synthalin B. Although its activity and safety have been improved, its toxicity is a serious problem that cannot be eliminated. Despite this, Synthalin A did not exit clinical applications until the early 1930s, and the use of Synthalin B in Germany continued until the mid-1940s.
Metformin was born in 1922, and the Irish chemist Werner and Bell first prepared this compound; several years later, animal experiments confirmed its hypoglycemic activity, and metformin did not show toxicity in animals, but it was not Conduct human trials on it. At the same time, insulin was discovered and used in clinical practice as a star drug for the treatment of diabetes at that time. People once thought that the use of insulin would completely end diabetes. Under such circumstances, it is naturally difficult for researchers to obtain metformin and other anthraquinone derivatives. Adequate attention.
➢ In-depth study and promotion of metformin
When metformin returned to people's field of vision, it has been another 20 years. In 1949, Filipino doctor Garcia believed that metformin had anti-infective, anti-viral, anti-malarial and antipyretic effects, and was used to treat the flu. It was also found to reduce blood sugar and cause no other adverse reactions.
The key person who really valued metformin was the French diabetes scientist Sterne. He studied the hypoglycemic effect of crotonine in his early years of school. He studied the hypoglycemic effect of biguanides in the French pharmaceutical company Aron Laboratories and Laennec Hospital in 1956. In 1957, Sterne confirmed metformin in clinical trials. The hypoglycemic effect is called "Glucophage" for metformin, meaning "Glucose eater". This name is used today. This result quickly attracted the attention of the medical community. In the same year, metformin began to be marketed as a substitute for insulin in France for the treatment of T2DM. In 1958, metformin was approved for use in the UK and in 1972 it was successfully marketed in Canada. At this time, two other biguanide drugs began to appear. In 1957, U.S. vitamin companies Ungar, Freedman and Shapiro discovered Phenformin and reported clinical trial results of its hypoglycemic effect; in 1958 Mehnert and Seitz reported the results of Buformin. Ciba-Geigy soon introduced phenformin to the market under the trade name DBI, and Ding Shuangqi was also successfully listed in Germany under the trade name Silubin. Due to the strong hypoglycemic effect of phenformin, it was popular, and metformin was only used in France. At that time, it did not receive more attention. In 1968, the results of the American University Joint Diabetes Research Program showed that phenformin increased the mortality rate of cardiovascular disease. The risk of lactic acidosis caused by phenformin in the 1970s was discovered by American scientists, and its mortality rate was high. The sales of phenformin began to decrease in the year. In 1976, the US FDA proposed a delisting proposal for phenformin. In 1977, the legal process was officially launched. By the end of 1978, phenformin was withdrawn from the United States. Due to the same biguanide compound, metformin was also seriously affected by this adverse reaction event, and once again fell into a difficult situation.
When people are still prejudiced against metformin, the final changes in the perception of this drug have been accompanied by changes in scientific thinking. At present, the concept of evidence-based medicine is deeply rooted in the hearts of the people. The practice of its thoughts provides a large number of empirical evidence for scientific research and clinical treatment, which not only greatly affects the decision-making of scientific research, medical activities and health in countries around the world, but also makes people aware of diseases, The understanding of drugs and medicine has revolutionized. Although the concept of evidence-based medicine was formally proposed in the 1990s, some long-term, large-sample, multi-center, randomized, large-scale clinical studies have actually begun very early.
It is generally believed that one of the first signs of the full application of evidence-based medicine in clinical practice research is the famous UK Prospective Diabetes Research (UKPDS) program in the field of diabetes research, which was hosted by Professor Turner and Professor Holman of the University of Oxford, UK. Design preparation began in 1976 and was officially launched in 1977. The study was conducted on 5102 T2DM patients in 23 clinical trials in the UK (the number of patients selected in the published study was 3867). The whole process ended in 1997 and lasted for 20 years. It is the longest medical study to date, and an epoch-making milestone in the history of diabetes treatment and even in the history of human medicine. In 1998, the official UKPDS report was published in the famous British medical journal Lancet. The blood glucose lowering effect of metformin was fully confirmed by a large number of clinical experiments, and its cardiovascular protective effect was also confirmed. This report has had a profound impact on the development of guidelines and guidelines for the prevention and treatment of diabetes worldwide, and has also promoted metformin as a first-line treatment for T2DM. In 1994, the US FDA approved metformin for the treatment of T2DM. In 1995, it was officially produced in the United States by Bristol-Myers Squibb Co..
➢ Conclusion
2017 is the 60th anniversary of the market launch of metformin. When the aura of “classic medicine” and “gold standard” is put aside, it is only in time to re-examine the development process of metformin, which will bring thoughts to researchers. Revelation.
In the era of empirical medicine, people have discovered the medicinal effects of goat beans from long-term practice. With the development of modern natural medicinal chemistry and biology, the monomeric compound of natto is extracted and obtained with steroids. The hypoglycemic effect was subsequently confirmed. Although metformin is not a natural product directly derived from nature, if there is no research accumulation and long-term concern about the natural product of crotonine, there may be no research boom in steroids in the early 20th century. Metformin was introduced as a derivative and thereafter. R&D and listing are even more difficult to talk about. Natural products have a wide range of sources and complex structures. They contain rich activities and diverse medicinal possibilities. As a gift from nature to human beings, natural products can inspire researchers' thinking and guide them even if they cannot directly become drugs. From another perspective, it provides important help for scientific research. The natural product-derived compounds are obtained by structural modification, chemical synthesis, etc., and are also commonly used methods for obtaining ideal drugs. The research process from goat beans to metformin is a good example.
In the history of the development of metformin, the results of clinical trials have played an important role. It was the clinical trial results of Sterne in 1957 that led to the marketing of metformin, and the results of clinical studies such as UGDP, which were affected by the reports of adverse reactions of biguanides, and the final confirmation of metformin was also the result of a large number of clinical trials of UKPDS. These long-term, large-scale clinical studies organized by relevant government departments are inevitable products of the development of medicine from the experience stage to the evidence-based stage. One of the important results is to make the safe and effective drugs such as metformin truly recognized.
➢ Reference material
1 Aluššík Š, Paluch Z. Metformin: The past, presence, and future [J]. MinervaMed, 2015, 106(4): 233-238.
2 Xu Yue, Cheng Jiefei. Research and development of small molecule drugs based on natural product derivation optimization
3 Mu Yiming, Ji Linong, Ning Guang et al. Expert agreement on the clinical application of metformin
Derivatization optimization of natural products can not only improve the dynamics of the body by changing the physicochemical properties such as solubility and stability of the compound, but also improve its activity and selectivity as a drug and reduce human toxicity. The natural product as a precursor for semi-synthesis of drugs and a template for chemical synthesis of drugs provides a broad idea for drug design.
Dimethylbiguanide (metformin) is a derivative of natural products and a basic drug for the treatment of type 2 diabetes mellitus (T2DM). It has been derived from long-term research on herbal goatpea and natural product. explore. Since its listing in 1957, metformin has been used for more than 60 years as a first-line drug, and its various hypoglycemic effects have been continuously discovered and confirmed. As an economical, safe and effective classic drug, it has always been I have not left the vision of medical workers and scientists, and have received more and more attention.
➢ Discovery of terpenoids
In medieval Europe, the above-ground parts of goat beans have been used as herbs to relieve polyuria, which is one of the typical symptoms of diabetes, which is also used in animal husbandry for animal lactation. In the 17th century, British botanist and physician Nicholas Culpeper (1616-1654) proposed that goat beans have anti-diabetic effects, and his views have attracted the attention of the British medical community and spread widely. In the 19th century, goat beans were introduced to the United States as pasture, but they were quickly found to be very toxic to livestock and even fatal, so they were included in the Federal Noxious Weed List. Goat beans are also harmful to the human body. During this period, it was found that goat beans contain a large amount of terpenoids, which are small molecules with three N atoms and strong alkalinity. Through animal experiments, scientists have discovered that steroids have hypoglycemic effects. This result was published in 1918, but because of the strong toxicity of terpenoids, researchers began to turn their attention to another compound in goat beans, namely goats. Beanine.
In 1914, the French scientist Tanret first extracted the gooseine (Galegine) from the goat bean seeds and conducted a preliminary study on the alkaloid; in 1923, Barger and White of Edinburgh, England, determined the chemical structure of the goat's base; 1925 In the year, German scientists Späth and Spitzy completed the chemical synthesis of crotonine; in 1927, Tanret continued to carry out pharmacological studies on natto, and in experimental animals (rabbits and dogs), crotonine showed sustained hypoglycemic effect and Serious toxic reaction; in the same year, German scientists Müller and Reinwein published the results of human clinical trials of crotonine. Three subjects showed hypoglycemia after taking crotonine. The blood glucose level was weaker in patients with normal blood sugar, while the blood sugar level in diabetic patients was lower. The effect is more obvious. Since then, many scholars have studied and explored the safety of improving the drug use of crotonine, and some progress has been made. However, in general, the difference in the therapeutic effect of crotonine and the short duration of action have limited its clinical application in the treatment of diabetes.
During this period, scientists synthesized a number of anthraquinone derivatives in order to obtain safe and effective treatment for diabetes drugs. In 1926, Frank et al. reported the hypoglycemic activity of a biguanide, decane biguanide. In the same year, Schering of Germany introduced it to the market under the trade name Synthalin A. In order to reduce its toxicity, Schering's other product, dodecane bismuth, was quickly introduced. The trade name is Synthalin B. Although its activity and safety have been improved, its toxicity is a serious problem that cannot be eliminated. Despite this, Synthalin A did not exit clinical applications until the early 1930s, and the use of Synthalin B in Germany continued until the mid-1940s.
Metformin was born in 1922, and the Irish chemist Werner and Bell first prepared this compound; several years later, animal experiments confirmed its hypoglycemic activity, and metformin did not show toxicity in animals, but it was not Conduct human trials on it. At the same time, insulin was discovered and used in clinical practice as a star drug for the treatment of diabetes at that time. People once thought that the use of insulin would completely end diabetes. Under such circumstances, it is naturally difficult for researchers to obtain metformin and other anthraquinone derivatives. Adequate attention.
➢ In-depth study and promotion of metformin
When metformin returned to people's field of vision, it has been another 20 years. In 1949, Filipino doctor Garcia believed that metformin had anti-infective, anti-viral, anti-malarial and antipyretic effects, and was used to treat the flu. It was also found to reduce blood sugar and cause no other adverse reactions.
The key person who really valued metformin was the French diabetes scientist Sterne. He studied the hypoglycemic effect of crotonine in his early years of school. He studied the hypoglycemic effect of biguanides in the French pharmaceutical company Aron Laboratories and Laennec Hospital in 1956. In 1957, Sterne confirmed metformin in clinical trials. The hypoglycemic effect is called "Glucophage" for metformin, meaning "Glucose eater". This name is used today. This result quickly attracted the attention of the medical community. In the same year, metformin began to be marketed as a substitute for insulin in France for the treatment of T2DM. In 1958, metformin was approved for use in the UK and in 1972 it was successfully marketed in Canada. At this time, two other biguanide drugs began to appear. In 1957, U.S. vitamin companies Ungar, Freedman and Shapiro discovered Phenformin and reported clinical trial results of its hypoglycemic effect; in 1958 Mehnert and Seitz reported the results of Buformin. Ciba-Geigy soon introduced phenformin to the market under the trade name DBI, and Ding Shuangqi was also successfully listed in Germany under the trade name Silubin. Due to the strong hypoglycemic effect of phenformin, it was popular, and metformin was only used in France. At that time, it did not receive more attention. In 1968, the results of the American University Joint Diabetes Research Program showed that phenformin increased the mortality rate of cardiovascular disease. The risk of lactic acidosis caused by phenformin in the 1970s was discovered by American scientists, and its mortality rate was high. The sales of phenformin began to decrease in the year. In 1976, the US FDA proposed a delisting proposal for phenformin. In 1977, the legal process was officially launched. By the end of 1978, phenformin was withdrawn from the United States. Due to the same biguanide compound, metformin was also seriously affected by this adverse reaction event, and once again fell into a difficult situation.
When people are still prejudiced against metformin, the final changes in the perception of this drug have been accompanied by changes in scientific thinking. At present, the concept of evidence-based medicine is deeply rooted in the hearts of the people. The practice of its thoughts provides a large number of empirical evidence for scientific research and clinical treatment, which not only greatly affects the decision-making of scientific research, medical activities and health in countries around the world, but also makes people aware of diseases, The understanding of drugs and medicine has revolutionized. Although the concept of evidence-based medicine was formally proposed in the 1990s, some long-term, large-sample, multi-center, randomized, large-scale clinical studies have actually begun very early.
It is generally believed that one of the first signs of the full application of evidence-based medicine in clinical practice research is the famous UK Prospective Diabetes Research (UKPDS) program in the field of diabetes research, which was hosted by Professor Turner and Professor Holman of the University of Oxford, UK. Design preparation began in 1976 and was officially launched in 1977. The study was conducted on 5102 T2DM patients in 23 clinical trials in the UK (the number of patients selected in the published study was 3867). The whole process ended in 1997 and lasted for 20 years. It is the longest medical study to date, and an epoch-making milestone in the history of diabetes treatment and even in the history of human medicine. In 1998, the official UKPDS report was published in the famous British medical journal Lancet. The blood glucose lowering effect of metformin was fully confirmed by a large number of clinical experiments, and its cardiovascular protective effect was also confirmed. This report has had a profound impact on the development of guidelines and guidelines for the prevention and treatment of diabetes worldwide, and has also promoted metformin as a first-line treatment for T2DM. In 1994, the US FDA approved metformin for the treatment of T2DM. In 1995, it was officially produced in the United States by Bristol-Myers Squibb Co..
➢ Conclusion
2017 is the 60th anniversary of the market launch of metformin. When the aura of “classic medicine” and “gold standard” is put aside, it is only in time to re-examine the development process of metformin, which will bring thoughts to researchers. Revelation.
In the era of empirical medicine, people have discovered the medicinal effects of goat beans from long-term practice. With the development of modern natural medicinal chemistry and biology, the monomeric compound of natto is extracted and obtained with steroids. The hypoglycemic effect was subsequently confirmed. Although metformin is not a natural product directly derived from nature, if there is no research accumulation and long-term concern about the natural product of crotonine, there may be no research boom in steroids in the early 20th century. Metformin was introduced as a derivative and thereafter. R&D and listing are even more difficult to talk about. Natural products have a wide range of sources and complex structures. They contain rich activities and diverse medicinal possibilities. As a gift from nature to human beings, natural products can inspire researchers' thinking and guide them even if they cannot directly become drugs. From another perspective, it provides important help for scientific research. The natural product-derived compounds are obtained by structural modification, chemical synthesis, etc., and are also commonly used methods for obtaining ideal drugs. The research process from goat beans to metformin is a good example.
In the history of the development of metformin, the results of clinical trials have played an important role. It was the clinical trial results of Sterne in 1957 that led to the marketing of metformin, and the results of clinical studies such as UGDP, which were affected by the reports of adverse reactions of biguanides, and the final confirmation of metformin was also the result of a large number of clinical trials of UKPDS. These long-term, large-scale clinical studies organized by relevant government departments are inevitable products of the development of medicine from the experience stage to the evidence-based stage. One of the important results is to make the safe and effective drugs such as metformin truly recognized.
➢ Reference material
1 Aluššík Š, Paluch Z. Metformin: The past, presence, and future [J]. MinervaMed, 2015, 106(4): 233-238.
2 Xu Yue, Cheng Jiefei. Research and development of small molecule drugs based on natural product derivation optimization
3 Mu Yiming, Ji Linong, Ning Guang et al. Expert agreement on the clinical application of metformin
