New pipeline for drugs that keep people young forever

Author:Dao tuo

           New pipeline for drugs that keep people young forever          

Longevity is the unremitting pursuit of human beings. At present, drugs have entered clinical trials and are likely to be listed in the next few years. The capital market also attaches great importance to the research and development of anti-aging drugs. There are large sums of money invested in this field. Major pharmaceutical companies have turned to anti-aging drugs, and startups have also grown rapidly. For example, Unity Biotechnology, resTORbio, CohBar and other pipeline drugs have entered the clinic. test. American biotechnology company resTORbio was established in 2016 to focus on human anti-aging drug development. Currently, two anti-aging mTORC1 inhibitors are in clinical trials. Unity Biotechnology was founded in 2011, and two drugs are in clinical phase I. CohBar was founded in 2007 and has a drug in clinical phase I.

Anti-aging drug research direction

Through short-lived animal model studies, more than 2,000 genes have an impact on the lifespan of the organism, and the pathways associated with each gene regulate the organism, which in turn affects the lifespan of the organism. For example, low levels of IGF signaling can lead to life-related diseases such as cancer, autoimmune diseases, Alzheimer's disease, etc. The genetic regulation of life span is very broad, including human nutrition, medicines, and daily cosmetics. Will affect the expression and regulation of genes. Hundreds of genes that regulate aging life have been identified, and most of the involved common signaling pathways, such as insulin signaling, autophagy, oxidative phosphorylation, and TOR signaling, are involved in the regulation of longevity. And prolonged life pathways are often evolutionarily conserved, destroying the insulin IGF1 pathway, prolonging the lifespan of yeast, worms, flies and mice, and IGF1R mutations are also associated with longevity in humans. Therefore, the signaling pathway of evolutionarily conserved genes is an important target for drug discovery.

The most striking examples are SIRT1 (a target for resveratrol) and TOR (a rapamycin target). After TOR is inhibited, their life span is extended, whether yeast or mammal. Later, people did clinical trials, but there was an accident. Novartis found that rapamycin increased the immune function of elderly volunteers, which led to serious side effects. The researchers then synthesized its analog, named "Rapalogs", and in 2017, Novartis handed the work over to ResTORbio. Other biotech companies have also introduced TOR inhibitors such as rapalog TAM-01 from Mount Tam Biotechnologies.

However, resveratrol is not as good as rapamycin. In 2008, GlaxoSmithKline (GSK) spent $720 million to buy Sirtris, a company that studies resveratrol. However, the results of the experiment made GSK disappointing. Resveratrol did not extend the life of the mouse study, after which the study was gradually shut down.

Mention of aging studies have to mention telomeres, a protein at the end of chromatin. In the mouse experiment, it shortened as the cells divide and age. Telomerase can regulate the length of telomeres. Overexpression of telomerase makes 24% of mice live above average and does not cause cancer. This is the experimental basis for the development of activated telomerase therapy. 

Telomere and chromatin (red part is telomere)

In addition, Everon Biosciences found that most of the cells expressing p16Ink4a are senescence-associated macrophages (SAMs) that are effective in removing senescent cells from the body. They then studied the SAMolytic factor to change the body's aging state. Siwa Therapeutics, on the other hand, focuses on the study of aging cell markers to identify and remove senescent cells. Some companies believe in the concept of protein homeostasis. Proteostasis Therapeutics specializes in developing drugs that control protein homeostasis, targeting genetic and degenerative diseases, but their first drug candidate, RT001, has been in clinical trials. failure. An analog of the mitochondrial MOTS-c peptide of Cohbar has begun clinical phase I trials.

Drugs entering clinical trials

Metformin is a drug for the treatment of type 2 diabetes, which reduces hepatic glycogen production and insulin sensitivity. Recent preclinical data show that it can increase nematode lifespan by 57%, increase lifespan by 6%, and increase lifespan by 2%. Its mechanism of action includes reducing DNA damage, cellular aging and mitochondrial oxidation. Although metformin is not as effective as other compounds, it is at least a safe drug from clinical data, and metformin is highly likely to be approved by the FDA for anti-aging use.

After the aging of the human body, the immune function declines inevitably. ResTORbio focuses on the study of the mTOR signaling pathway. It has been mentioned that the TOR inhibitor affects the life span, which is an evolutionary conservative pathway regulating aging and enhances the human immune response. . The company focuses on the development of RTB101, an oral mTORC1 inhibitor that can be used alone or in combination with other mTOR inhibitors to improve the immune function of the elderly and reduce the incidence of diseases such as respiratory infections in the elderly. In July of this year, the results of Phase IIb clinical trials showed that the respiratory infection rate of 652 elderly volunteers decreased by 30%.

In the late 19th century, Weismann believed that cells might have limited potential for division. In the 1960s, Leonard Hayflick discovered that many cells lost their ability to divide after 50 divisions. According to this theory, selectively killing senescent cells that have stopped dividing will prolong the life of the organism. Unity Biotechnology is dedicated to the development of selective aging-removing cells, with a focus on topical treatment for osteoarthritis, ophthalmology and lung infections. UBX0101 is a therapeutic drug for osteoarthritis and is currently in clinical phase I trials. Studies have shown that UBX0101 induces apoptosis in senescent cells by blocking the anti-apoptotic interaction between MDM2 and p53. UBX1967 is mainly used for ophthalmic diseases, including diabetic retinopathy, glaucoma and age-related macular degeneration.

Cohbar is primarily focused on age-related metabolic disorders in the body. Its representative drug CB4211 has undergone phase I clinical trials. CB4211 is a novel MOTS-c analog, a natural mitochondrial polypeptide discovered in 2012. MOTS-c plays an important role in metabolic regulation, and has the effect of promoting metabolic homeostasis and reducing obesity and insulin resistance. In preclinical studies, CB4211 has been shown to have significant therapeutic potential for the treatment of NASH (steatohepatitis), improve triglyceride levels, and has NAFLD (nonalcoholic fatty liver) and NASH-related liver enzyme markers and obesity. The beneficial effect is that it has a stronger weight loss effect than the weight-loss drugs sold in the market.

Anti-aging drug development prospects

Although we already know that more than 2,000 genes have life-regulating effects, and more than 400 compounds have prolonged lifespan of model organisms, humans are not nematodes or mice, and perhaps miraculous drugs in animals are one in the human body. Heap "garbage". Although we have advanced pharmacological experimental techniques, most of the drugs are poorly reproducible in the human body. The observation time of aging is relatively long, and the clinical funds need to increase with time, each of which restricts the development of anti-aging drugs. Fortunately, the emergence of new technologies has reduced the barriers to drug development, and the clinical trials of the first class of drugs will provide valuable experience for the development of later drugs.

Reference materials:

1.The Business of Anti-Aging Science

2.Anti-ageing pipeline starts to mature

3. Genome-EnvironmentInteractions That Modulate Aging: Powerful Targets for Drug Discovery

4.https://www.cohbar.com

5.https://www.restorbio.com

6.https://unitybiotechnology.com

This article is reproduced from：https://news.pharmacodia.com/news/html/info/info-detail.html?id=29161

Longevity is the unremitting pursuit of human beings. At present, drugs have entered clinical trials and are likely toLongevity is the unremitting pursuit of human beings. At present, drugs have entered clinical trials and are likely to be listed in the next few years. The capital market also attaches great importance to the research and development of anti-aging drugs. There are large sums of money invested in this field. Major pharmaceutical companies have turned to anti-aging drugs, and startups have also grown rapidly. For example, Unity Biotechnology, resTORbio, CohBar and other pipeline drugs have entered the clinic. test. American biotechnology company resTORbio was established in 2016 to focus on human anti-aging drug development. Currently, two anti-aging mTORC1 inhibitors are in clinical trials. Unity Biotechnology was founded in 2011, and two drugs are in clinical phase I. CohBar was founded in 2007 and has a drug in clinical phase I.

Anti-aging drug research direction

Through short-lived animal model studs, more than 2,000 genes have an impact on the lifespan of the organism, and the pathways associated with each gene regulate the organism, which in turn affects the lifespan of the organism. For example, low levels of IGF signaling can lead to life-related diseases such as cancer, autoimmune diseases, Alzheimer's disease, etc. The genetic regulation of life span is very broad, including human nutrition, medicines, and daily cosmetics. Will affect the expression and regulation of genes. Hundreds of genes that regulate aging life have been identified, and most of the involved common signaling pathways, such as insulin signaling, autophagy, oxidative phosphorylation, and TOR signaling, are involved in the regulation of longevity. And prolonged life pathways are often evolutionarily conserved, destroying the insulin IGF1 pathway, prolonging the lifespan of yeast, worms, flies and mice, and IGF1R mutations are also associated with longevity in humans. Therefore, the signaling pathway of evolutionarily conserved genes is an important target for drug discovery.

The most striking examples are SIRT1 (a target for resveratrol) and TOR (a rapamycin target). After TOR is inhibited, their life span is extended, whether yeast or mammal. Later, people did clinical trials, but there was an accident. Novartis found that rapamycin increased the immune function of elderly volunteers, which led to serious side effects. The researchers then synthesized its analog, named "Rapalogs", and in 2017, Novartis handed the work over to ResTORbio. Other biotech companies have also introduced TOR inhibitors such as rapalog TAM-01 from Mount Tam Biotechnologies.

However, resveratrol is not as good as rapamycin. In 2008, GlaxoSmithKline (GSK) spent $720 million to buy Sirtris, a company that studies resveratrol. However, the results of the experiment made GSK disappointing. Resveratrol did not extend the life of the mouse  be listed in the next few years. The capital market also attaches great importance to the research and development of anti-aging drugs. There are large sums of money invested in this field. Major pharmaceutical companies have turned to anti-aging drugs, and startups have also grown rapidly. For example, Unity Biotechnology, resTORbio, CohBar and other pipeline drugs have entered the clinic. test. American biotechnology company resTORbio was established in 2016 to focus on human anti-aging drug development. Currently, two anti-aging mTORC1 inhibitors are in clinical trials. Unity Biotechnology was founded in 2011, and two drugs are in clinical phase I. CohBar was founded in 2007 and has a drug in clinical phase I.

Anti-aging drug research direction

Through short-lived animal model studies, more than 2,000 genes have an impact on the lifespan of the organism, and the pathways associated with each gene regulate the organism, which in turn affects the lifespan of the organism. For example, low levels of IGF signaling can lead to life-related diseases such as cancer, autoimmune diseases, Alzheimer's disease, etc. The genetic regulation of life span is very broad, including human nutrition, medicines, and daily cosmetics. Will affect the expression and regulation of genes. Hundreds of genes that regulate aging life have been identified, and most of the involved common signaling pathways, such as insulin signaling, autophagy, oxidative phosphorylation, and TOR signaling, are involved in the regulation of longevity. And prolonged life pathways are often evolutionarily conserved, destroying the insulin IGF1 pathway, prolonging the lifespan of yeast, worms, flies and mice, and IGF1R mutations are also associated with longevity in humans. Therefore, the signaling pathway of evolutionarily conserved genes is an important target for drug discovery.

The most striking examples are SIRT1 (a target for resveratrol) and TOR (a rapamycin target). After TOR is inhibited, their life span is extended, whether yeast or mammal. Later, people did clinical trials, but there was an accident. Novartis found that rapamycin increased the immune function of elderly volunteers, which led to serious side effects. The researchers then synthesized its analog, named "Rapalogs", and in 2017, Novartis handed the work over to ResTORbio. Other biotech companies have also introduced TOR inhibitors such as rapalog TAM-01 from Mount Tam Biotechnologies.

However, resveratrol is not as good as rapamycin. In 2008, GlaxoSmithKline (GSK) spent $720 million to buy Sirtris, a company that studies resveratrol. However, the results of the experiment made GSK disappointing. Resveratrol did not extend the life of the mouse study, after which the study was gradually shut down.

GMP Manufacturer，Dulaglutide（923950-08-7）

EOS med chem works with you to know about Dulaglutide ↴

↠ Background:

Dulaglutide (doo" la gloo' tide) is a glucagon-like peptide-1 (GLP-1) analogue that acts like the native gastrointestinal hormone (incretin) to increase insulin secretion.  Dulaglutide reproduces the activity of GLP-1, binding to specific receptors on pancreatic beta cells and increasing insulin secretion, which can lead to improvement of glycemic control in patients with type 2 diabetes.  Dulaglutide, like other GLP-1 analogues, also causes weight loss which may contribute to its clinical effects.  Dulaglutide is a recombinant DNA produced polypeptide that shares 97% homology to endogenous human GLP-1(7-37), but has an amino acid substitution which makes it resistant to DPP-4 degradation and thus extends its half-life in serum.  In addition, the GLP-1 like polypeptide is linked to an Fc fragment of human IgG4 which further prolongs its serum half-life and duration of activity.  Dulaglutide, like other GLP-1 analogues, must be given parenterally.  Dulaglutide was approved for use in the United States in 2014 and current indications are for management of glycemic control in adults with type 2 diabetes in combination with diet and exercise, with or without other oral hypoglycemic agents.  Dulaglutide is available under the brand name Trulicity in solution for subcutaneous injection in prefilled, single dose pens or syringes (0.75 and 1.5 mg/0.5 mL).  The typical initial dose is 0.75 mg once weekly, which can be increased to 1.5 mg weekly.  Dulaglutide is generally well tolerated, but side effects can be dose limiting and include nausea [~20%], vomiting [~5%], diarrhea [~12%], abdominal pain, decreased appetite, dyspepsia and fatigue.  Rare side effects include pancreatitis [0.1-0.3%], hypoglycemia and hypersensitivity reactions.

↠ Introduction:

Dulaglutide is a recombinant DNA produced polypeptide analogue of human glucagon-like peptide-1 (GLP-1) which is used in combination with diet and exercise in the therapy of type 2 diabetes, either alone or in combination with other antidiabetic agents.  There have been no published reports of hepatotoxicity attributed to dulaglutide therapy.

Name Dulaglutide

CAS: 923950-08-7

sequence:

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp- Leu-Val-Lys-Gly-Gly-Gly

Purity: >98%

Molecular formula: C149H221N37O49

Molecular weight: 3314.62

Protein structure:

We have more than 50g in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

↠ Medical uses:

The compound is indicated for adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control. Dulaglutide is not indicated in the treatment of subjects with type 1 diabetes mellitus or patients with diabetic ketoacidosis because these problems are the result of the islet cells being unable to produce insulin and one of the actions of Dulaglutide is to stimulate functioning islet cell to produce more insulin. Dulaglutide can be used either stand-alone or in combination with other medicines for type 2 diabetes, in particular metformin, sulfonylureas, thiazolidinediones, and insulin taken concomitantly with meals.[4][non-primary source needed]

As of 2017 it is unclear if they affect a person's risk of death.

↠ Mechanism of action:

Dulaglutide binds to glucagon-like peptide 1 receptors, slowing gastric emptying and increases insulin secretion by pancreatic Beta cells. Simultaneously the compound reduces the elevated glucagon secretion by inhibiting alpha cells of the pancreas, which is known to be inappropriate in the diabetic patient. GLP-1 is normally secreted by L cells of the gastrointestinal mucosa in response to a meal.

Why choose EOS med chem ?

EOS med chem is the only manufacturer that provides excellent quality chemistry products and services at affordable rates. The experts working here are highly trained to handle these chemicals used in the creation of medicines used for treating various life-threatening diseases. We are into the manufacturing of chemical products after doing a deep research for the same.

EOS team of experts holds the work experience of more than ten years, and therefore we can assure you about the quality and superiority of the products and services we offer to all our valued clients around the globe. At present, this organization is listed among the most leading pharmaceutical suppliers around the world. We always supply products keeping the affordability in mind.

If necessary, you can contact us through the contact information below. Look forward to working with you.

EOS Med Chem, Medchem is Big
執大象，天下往，往而無害，安平泰
WEB: www.eosmedchem.com
EMAIL: info@eosmedchem.com; eosmedchem@gmail.com; eosmedchem@qq.com
TEL: 0086-531-69905422
GMP PLANT: No. 37, Yulong Road, Qufu City, Shandong Province.

↠ References

1.Courtney Aavang Tibble; Tricia Santos Cavaiola; Robert R Henry (2013). "Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes: A Review of Current Literature". Expert Rev Endocrinol Metab. 8 (3): 247–259. doi:10.1586/eem.13.20.

2. "Lilly's Once-Weekly Dulaglutide Shows Non-Inferiority to Liraglutide in Head-to-Head Phase III Trial for Type 2 Diabetes" (Press release). Eli Lilly. Feb 25, 2014.

3 ."FDA approves Trulicity to treat type 2 diabetes" (Press release). FDA. Sep 18, 2014.

4. Terauchi Y, Satoi Y, Takeuchi M, Imaoka T (July 2014). "Monotherapy with the once weekly GLP-1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled study". Endocr. J. 61: 949–59. doi:10.1507/endocrj.ej14-0147. PMID 25029955. Retrieved 2014-09-29.[non-primary source needed]

5.Liu, J; Li, L; Deng, K; Xu, C; Busse, JW; Vandvik, PO; Li, S; Guyatt, GH; Sun, X (8 June 2017). "Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis". BMJ (Clinical research ed.). 357: j2499. doi:10.1136/bmj.j2499. PMC 5463186 . PMID 28596247.

6. Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z (August 2014). "Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5)". Diabetes Care. 37 (8): 2149–58. doi:10.2337/dc13-2761. PMC 4113177 . PMID 24742660. Retrieved 2015-03-01.

7.Amblee A (April 2014). "Dulaglutide for the treatment of type 2 diabetes". Drugs Today. 50 (4): 277–89. doi:10.1358/dot.2014.50.4.2132740. PMID 24918645.

8. Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E (February 2014). "Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials". Diabetes Res. Clin. Pract. 103 (2): 269–75. doi:10.1016/j.diabres.2014.01.010. PMID 24485345.

9. Samson SL, Garber A (April 2013). "GLP-1R agonist therapy for diabetes: benefits and potential risks". Curr Opin Endocrinol Diabetes Obes. 20 (2): 87–97. doi:10.1097/MED.0b013e32835edb32. PMID 23403741. Retrieved 2014-09-30.

10. Nadkarni P, Chepurny OG, Holz GG (2014). "Regulation of glucose homeostasis by GLP-1". Prog Mol Biol Transl Sci. 121: 23–65. doi:10.1016/B978-0-12-800101-1.00002-8. PMC 4159612 . PMID 24373234.

Deoxycholic Acid/Kybella®

➼  Basic Information

Deoxycholic Acid/Kybella® is the world's first topical lipolysis drug approved by the US Food and Drug Administration (FDA) on April 29, 2015. The drug is developed, produced and marketed by Kythera Biopharmaceuticals, a subsidiary of Allergan.

Deoxycholic acid injection is approved for the treatment and improvement of bulges or plump (double chin) in adults with moderate to severe axillary fat. Kybella® is a subcutaneous injection containing 10 mg/mL deoxycholic acid, 2 mL per vial. The recommended dose is 0.2 mL of deoxycholic acid injection per subcutaneous injection. In the planned injection area, each interval is 1 cm, and no more than 50 injection points or 10 mL of deoxycholic acid injection per administration. A maximum of 6 single treatments can be performed at intervals of not less than 1 month.

➾ Structural formula：

   

➾ Mechanism

Deoxycholic acid is a free bile acid present in bile. It has strong surface activity and can destroy and dissolve cell membranes, so that a small amount of local subcutaneous fat dissolution is reduced.

⟹ Synthetic route：

⟹ Research key data

⟹ Research and marketing drugs with the same target：

Diabetes Buster: A classic legend of natural product research

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

Brief introduction to the status and trends of anti-tumor drug research and development

Author:Dao tuo

Cancer is still the number one killer of human health. According to the National Institutes of Health (NIH), in 2012, there were 14.1 million new cases worldwide and 8.2 million cancer-related deaths. In 2012, 57% of new cancer cases occurred in less developed regions of the world, including Central America and parts of Africa and Asia, and 65% of cancer deaths also occurred in these areas. In 2018 alone, there are more than 1.7 million new cases of cancer. By 2030, the number of new cancer cases is expected to increase to 23.6 million per year.



In recent years, the benefits of anti-cancer drugs have increased. In 2017, global cancer treatment costs have exceeded $133 billion, an increase of nearly $96 billion over 2013. According to some studies, in the next five years, research and development funds in this field can reach 18-200 billion US dollars, with a compound annual growth rate of 10%-13%.

In the past 5 years, 63 anti-tumor drugs have been approved, covering 24 different tumor types. In 2017, 14 drugs were approved for marketing, 11 of which were granted FDA-approved breakthrough therapy, and the overall response rate of this group of drugs exceeded 50%, significantly improving patient survival and improving patients' quality of life. Since the introduction of PD-1 and PD-L1 inhibitors in 2014, they have already occupied a large share. The market prospects are still broad in the future. By 2017, these drugs have been used in the treatment of 23 kinds of cancers, and for the first time for lung cancer. 


⧫ Clinical research pipeline

Currently, more than 700 drugs are undergoing clinical trials, an increase of 60% from a decade ago. More than 33% of the drugs are guided by the patient's biomarkers in clinical trials, which is more reasonable and accurate than previous clinical trials. In Phase I or Phase II clinical trials, nearly half of the drugs are related to immunotherapy, covering 34 tumor types. In 2016, the success rates of Phase I and Phase III clinical trials were 66% and 73%, respectively, while the success rate of Phase II trials was only 30%. From the time of clinical trials, the duration of the entire clinical trial and the number of people required are decreasing. Among the drugs approved in 2017, the time from patent application to drug approval was 14 years, slightly faster than 2013.


⧫ Immunological checkpoint inhibitor

Immune cells can effectively kill tumor cells, but some tumor cells destroy the signaling pathway of immune checkpoints involved in PD-1 (programmed death protein-1). PD-1 inhibitors can help eliminate tumor cells that overexpress PD-1 protein and escape immune surveillance. Following the launch of Ipilimumab (an anti-CTLA4 drug) in 2011, two highly anticipated anti-PD-1 drugs (Keytruda and Opdivo) were introduced at the end of 2014 for the treatment of melanoma. In 2016, the US FDA approved Genentech's Atezolizumab for the treatment of bladder cancer and non-small cell lung cancer. In 2017, Avelumab, developed by Pfizer, was approved for marketing for metastatic cell carcinoma (Merkel cell carcinoma, a rare and highly aggressive skin cancer) that was approved for metastatic bladder at the end of the year. Treatment of cancer. In the same year, AstraZeneca's Durvalumab was approved for metastatic urothelial cancer.

As a new type of therapy, immunological checkpoint inhibitors have broad room for development. In 2017, these drugs have been used in the treatment of 23 kinds of cancers, and for the first time for the treatment of lung cancer. Most of the drugs approved by the US FDA are used to treat melanoma, bladder cancer, lung cancer, etc., and more than half of these therapies are used for the treatment of lung cancer. Both Keytruda and Opdivo can be used for chemotherapy for lung cancer, and Keytruda is First-line medication. The use of immunosuppressive point combination therapy is becoming more common in the treatment of melanoma.



Next-generation immunological checkpoint inhibitors have more than 300 drugs in clinical trials at various stages, most of which are CTLA4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CD19/CD3 antibodies, IDO (Indoleamine- Pyrrole-2,3-dioxygenase) inhibitor. Among them, PD-1/PD-L1 accounted for the most, reaching 58%, and about 8% of CD19/CD3 antibodies were in Phase I or Phase II clinical trials. 17% of IDO inhibitors are in clinical phase III trials, and 2% are in phase I or phase II clinical trials.



In addition to immunological checkpoint inhibitors, other therapies such as vaccines, carT cell therapy, oncolytic viruses, and the like. At present, carT cell therapy such as Tisagenlecleucel and Axicabtagene ciloleucel specifically target B lymphocyte CD19 for the treatment of refractory B cell acute lymphocytic leukemia and diffuse large B cell lymphoma. Second-generation carT cell therapy is still under investigation, with approximately 90% of patients having symptoms resolved.



⧫ Top 5 best-selling drugs in the next 6 years

In the next six years, Keytruda's sales will exceed Revlimid, more than $12 billion, with a compound annual growth rate of 19%, ranking first among the best-selling anti-cancer drugs. Revlimid's patents will expire in 2019, when generics will compete with them, and Revlimid's sales pressure will increase, but the drug has a wide range of indications that will continue to maintain its dominance for some time to come. It is estimated that sales in 2024 will reach 11.9 billion US dollars, with a compound annual growth rate of 6%, ranking second. In the third place, Opdivo, which has the same target as Keytruda, is a PD-1 inhibitor with sales of $5.7 billion in 2017. It is expected to generate $11.4 billion in sales in 2024. The rate is 10%. In the fourth place is Imbruvica, the first listed Bruton's tyrosine kinase (BTK) inhibitor. With sales of $3.1 billion in 2017, it is expected to have annual sales of $9.6 billion in 2024, a compound annual growth rate of 17%. In fifth place, Ibrance, a CDK 4&6 (Cyclin-dependent kinases 4&6) inhibitor, was approved by the US FDA in May 2017. Its 2017 sales were $3.1 billion, and its sales are expected in 2024. It is $8.3 billion.









⧫ Summarize

Anti-tumor drug development is a hot area for drug development, not only because of its large audience, but also because of its high investment efficiency. In 2017, there were more than 700 clinical trials of anti-tumor drugs, and half of them were immunotherapy. It can be seen that immunotherapy has broad application prospects. At present, the PD-1 inhibitors Keytruda and Opdivo have great growth potential and will be among the forefront of anti-tumor drugs in the next few years. The research on CD19 inhibitor drug JCAR017 is currently in the phase II clinical stage, and it is likely to be successful in the next few years, and it has a broad space for development.

Reference：

1. Global Oncology Trends 2018

2. EvaluatePharma World Preview 2018, Outlook to2024

3. https://www.nih.gov/

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Oseltamivir era drug - Roche Baloxavir marboxil

Author: W & D

Introduction

Influenza (referred to as influenza) is an acute respiratory infection caused by influenza virus, and it is also a disease that is highly contagious and spreads rapidly. It is mainly transmitted by droplets in the air, contact between people or contact with contaminated objects.

At the beginning of the year, an article "Beijing Middle Age under the Influenza" caused widespread concern in the whole society. Let us realize that sometimes it is also a fatal blow to think of "small illnesses and catastrophes" and "cold". The flu is a common disease that can pose a serious threat to public health. Its virus is highly variable and prone to drug resistance. About 3 to 5 million patients worldwide are severely affected by the flu each year, millions of patients need hospitalization, and about 650,000 patients die.

At present, drugs for the treatment of influenza can be roughly classified into two types according to their targets: M2 inhibitors (amantadine hydrochloride, rimantadine hydrochloride) and neuraminidase inhibitors (zanamivir, phosphate ose Hewei, Palamivir, etc.) Among these drugs, there are 79 companies producing amantadine hydrochloride, 7 companies in ruthenium HCl, 3 in oseltamivir phosphate, and only Roche. 1 home. The effective rate of the above two types of inhibitors for influenza chemoprevention is 70% to 90%. Due to the long-term, high-volume use of M2 inhibitors, drug resistance is becoming more and more serious, and it is expected that neuraminidase inhibitors will not escape serious drug resistance problems. This puts urgent demands on the emergence of new targets and new mechanisms of action. Baloxavir marboxil, which was approved as a new mechanism of action, was qualified for listing in Japan in February this year. It was recently applied by Roche and obtained the FDA's priority for evaluation. The drug was developed by Japan's Yan Yeyi and will be removed from Japan and China in 2016. The development rights outside Taiwan were transferred to Roche. Due to the large number of influenza infections each year, the drug market has great market potential, and compared with oseltamivir, the drug is simple to use, one tablet at a time, no need for treatment, clinical trials show that the drug's effect is Better than oseltamivir, it is expected to reach and surpass oseltamivir in sales. It is expected that Roche will be able to obtain the approval conclusion given by the FDA by the end of this year. The drug is expected to become a trump card in the field that Roche continues to lead in the future.

➠ Basic information about drugs:

English name: Baloxavir marboxil (S-033188)

Molecular formula: C₂₇H₂₃F₂N₃O₇S

Structure:

  Mechanism of drug action: Unlike the mechanism of action of M2 inhibitors and neuraminidase inhibitors, this drug is a new mechanism of action in recent years. The figure on the right reveals the mechanism of action of the anti-influenza virus. Baloxavir marboxil inhibits the CAP structure of the 5' end of the mRNA from the host cell during the replication process by interacting with the CAP-dependent endonuclease, thereby achieving the inability of the viral mRNA to be transcribed. The purpose is not to affect the host cell.

➠ Compound preparation method

The structural formula of the compound is relatively complicated. From the literature review, the reported synthetic route is also complicated, and the number of reaction steps is large.

First, compound 6 is reacted with allyl chloroformate under the action of n-butyllithium at -78 ° C to obtain compound 7, which is then reduced and etherified to give fragment compound 4; chloromethyl chloroformate and compound 10 at room temperature. The esterification reaction is carried out for 1 h to obtain the fragment compound 3; then the synthesis of the key compound 19 is carried out, and the compound 11 is reacted with ethyl iodide to obtain the compound 12 in a solution of dimethylacetamide with pyridinium p-toluenesulfonate and Boc肼 was reacted at 60 ° C for 14 h to obtain compound 13, and then Boc was obtained to obtain compound 14, and then compound 4 was obtained in the same manner. In the acetonitrile at -25 ° C, tin tetrachloride was added dropwise and stirred for 45 min. Compound 15 is obtained, followed by the addition of morpholine and tetrakis(triphenylphosphine)palladium to give compound 16 which is chirally resolved to give compound 19 which is further combined with 7,8-difluoro-6,11 - Dihydrodibenzothiazepine-11-ol is reacted to give compound 20, which is deprotected to give compound 2, which is then reacted with compound 3 previously obtained to give compound 1 - Baloxavir marboxil. The above content is a synthetic route compiled according to the WO2016175224 patent. As can be seen from the above, the synthesis method is complicated, and the methods of the remaining two patent reports are not described herein.

➠ Summary

As the only new antiviral drug with a new mechanism of action in recent years, its approval in Japan and the FDA's priority review in June this year have shown its good treatment and market prospects. With the increased risk of drug resistance, Roche has shown sufficient confidence in the drug that it will replace oseltamivir in the future and become the next star drug against influenza. Whether it is exactly what it says, it will be known in the near future.

References:

1. Http://www.shionogi.co.jp/

2. Http://www.medsci.cn

3. Https://analytics.zhihuiya.com/

4. Innovation andtrends in the development and approval of antiviral medicines: 1987–2017 andbeyond. S. Chaudhuri et al. Antiviral Research 155 (2018) 76–88

5. WO2016175224

6. WO2017221869

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