Why did Johnson & Johnson, Pfizer, etc. choose the same technology to develop small molecule new drugs?

1. How do multinational pharmaceutical companies solve the problem of low return on investment?

In 2017, GSK shut down Shanghai Zhangjiang's neurological disease research and development center; Lilly Pharmaceuticals closed Shanghai Zhangjiang's China R&D center;

In 2016, Novartis closed the cell and gene therapy division;

In 2015, Aberdeen closed the Kidney Disease Research Center.

......

Compared with the prosperity of multinational pharmaceutical companies in the past 15 years to establish R&D centers in China, in recent years, multinational pharmaceutical companies have greatly reduced or even closed their R&D centers and investment resources in China, which makes people worry about the prospects of new drug research and development.

According to a report released by Deloitte in December 2017, the return on investment for new drug research and development in 2017 was only 3.2%, and the cost of listing a new drug was as high as $1.99 billion.

In addition to huge research and development investment, when the new drug is launched, the initial patent protection period of the compound is also very low. The patent protection period that can be seen at the bottom does not even support the peak of new drug sales, and it faces the siege and patent challenge of generic drugs.

Under the premise of ensuring the quality of new drugs, how to shorten the research and development cycle and improve the success rate has become a topic of concern for all pharmaceutical people. Whether it is cooperative research and development, IP-VC-CRO, overall outsourcing and other models, or in-depth research on targets, improve screening techniques and other means, scientists are actively trying.

In June 2018, AstraZeneca scientists counted 66 new drug development articles published in the Journal of Medicinal Chemistry from 2016 to 2017 to explore commonly used drug discovery strategies, summarizing five commonly used techniques, including based on known structures. Derivative methods for compounds, random high-throughput screening, structure-based drug design, fragment-based lead compound discovery, and DNA-coding compound library screening. Among them, the DNA coding compound library technology is one of the emerging technologies in the research and development of new drugs. It has achieved great development in the past few years and is favored by large pharmaceutical companies and investors at home and abroad.

It has been reported that AstraZeneca has stated that the use of DEL technology is one of the reasons for the improvement of its research and development productivity.

Analysis of DNA coding compound library technology related literature collected by PubMed database from July to July 2018. In academia and industry, the research and application of DNA coding compound library technology has been on the rise since 2012, many based on DEL. The development of new drug developments in technology, large-scale transaction cooperation, and companies engaged in DNA-coded compound libraries have also emerged intensively since this time. Large-scale cooperative transactions such as Sanofi and DICE contracted a total of $2.3 billion in new drug research and development cooperation.

Literature Classification Based on DNA-Coded Compound Library Technology in Pubmed in 1992-2018

According to further statistics, 19 of the top 20 global pharmaceutical companies (ranked by 2016 sales) use DNA coding compound library technology to develop new drug development through external cooperation or internal research and development.

2. DNA coding compound library technology empowers new drug development

The traditional compound library is limited by the high synthesis cost of the compound, the large storage space requirement, the strict screening requirements and the high degree of automation requirements. The capacity of the compound library available for screening is often in the order of one million. An important condition for the discovery of lead compounds is the need for a sufficient number of compounds to be screened. Large compound libraries often require decades of accumulation and substantial ongoing capital investment. For companies that are committed to new drug development in China, it is not optimal to build a multi-million-level compound library using conventional methods. But the scientists' pursuit of a larger chemical space has never stopped, and they have gathered their attention in the field of DNA-coded compound library technology.

The discovery of RIP1 inhibitors is a typical example of the application of DNA-encoding compounds.

At the beginning of the project, GlaxoSmithKline scientist Harris et al. used a fluorescence polarization screening method to screen a kinase library containing 40,000 compounds, and used a high-throughput screening technique to screen a library containing 2 million compounds. Lead compound. Finally, 7.7 billion compounds were screened by DNA-encoding compound library technology, and GSK481, a target compound that specifically binds to the RIP1 target and efficiently blocks TNF-dependent cellular pathways, was obtained in one go. In the subsequent optimization process, only the two atoms on the heterocycle were modified and directly entered the clinic. Currently, the compound is in phase II clinical study.

Compared with the traditional technology, the DNA coding compound library can not only reach a wider chemical space, but the requirements for reagents, hardware facilities and the like are relatively easier to implement, and the synthesis and screening costs are significantly reduced.

Compared with traditional technology, DEL technology not only has advantages in screening compound quantity and cost, but also has advantages in screening efficiency and time.

It usually takes only a few weeks to synthesize a library of DNA-coding compounds, and it takes only a few months to screen a billion-dollar compound, which greatly shortens the cycle of discovery of new drugs. In addition, the technology can quickly and efficiently discover new structural compounds against mature targets, avoiding low levels of duplication; targeting traditionally considered small molecule drug-making targets can screen for target compounds, such as PPI-like targets, IL17 targets; The target can efficiently find the StartingPoint, which provides the possibility to quickly carry out subsequent research to seize the opportunities in this field.

 

DNA-encoding compound library technology enables screening of traditional targets, challenging targets and emerging targets and successful production of high-quality target compounds

Med.Chem.Commun.,2016,7,1898-1909

3. China's strategy to cope with the crisis of new drug research and development

The DNA-encoding compound library technology is a multidisciplinary and highly integrated technology platform. At present, X-Chem, Nuevolution and HitGen (Chengdu Pilot), which are capable of providing large-scale research and development of new drugs based on DNA-encoded compound libraries, are available worldwide.

Among them, as the first biotechnology company in China to develop new drugs based on DNA-encoded compound library technology, since 2015, the company has disclosed 22 new drug research and development partners, including many of them expanding cooperation with Pfizer and Merck.

Globally, according to the incomplete statistics of public data of various companies' websites, the number of new drug research and development cooperation based on DNA-coded compound library technology has been 64 in the world since 2015, and the number of Chengdu-leading cooperation accounts for 34.4%. X-Chem 25% of the total, Denmark Nuevolution accounted for 12.5%.

 

2015-2018 Cooperative distribution of globally published DNA-based compound library technology

(Total number of global public transactions: 64)

DNA-encoding compound library technology can screen for high-quality lead compounds that other technologies may miss for a certain disease mechanism, ensuring the breadth of screening and improving the efficiency of screening. It is a biotechnology company or a transformational biotechnology company in China that is committed to new drug development. Traditional pharmaceutical companies have provided new solutions for the deployment of new drugs at low cost and high efficiency in the layout of hot targets or emerging targets.

4. Conclusion: Innovation leads the future

The fundamental purpose of new drug research and development is to continuously find new molecular entities that can effectively regulate disease targets in diseases that do not meet the therapeutic needs. Although in the long struggle against disease, human beings have successfully converted many malignant diseases into chronic diseases, many chronic diseases have been cured, but this war is far from over, and more "stubborn" diseases have been discovered and become affected with the development of science and technology. A new threat to the quality of human life.

In the face of new challenges, innovation is imperative.

As the title has raised, 19 of the top 20 pharmaceutical companies in the world have chosen to use DNA-encoded compound library technology to lay out new drug developments. On the one hand, they prove the great potential of this technology in the development of new drugs, on the other hand, it is also pointed out in the severe In the face of challenges, even multinational pharmaceutical companies, using innovative technologies for new drug research and development is an important means to quickly achieve corporate strategic goals.

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Canagliflozin/Canaglu®

⇢ Basic Information 

Cagliar was approved by the US Food and Drug Administration (FDA) on March 29, 2013 and was approved by the European Medicines Agency (EMA) on November 15, 2013, on July 4, 2014. It was approved by the Japan Pharmaceutical Medical Device Integration Agency (PMDA) and was approved by the China Food and Drug Administration (CFDA) on September 29, 2017. The drug was originally researched by Tanabe Mitsubishi Pharmaceuticals. Johnson & Johnson's Yangsen Pharmaceutical was authorized by the US and the European Union in 2012. The drug is marketed in the US market under the trade name Invokana®. The Japanese region is produced and sold by Tanabe Mitsubishi, and is promoted jointly by the First Sankyo Co., Ltd. On March 7, 2018, Tai Tien Pharma, a subsidiary of Japan's Tanabe Mitsubishi, was sold under the trade name Canaglu® in Taiwan. The market was also launched by Tanabe Mitsubishi after the launch of Canaglu®. The second market.

Cagliflozin is a sodium-glucose transporter 2 (SGLT2) inhibitor. 90% of renal glucose reabsorption is achieved by SGLT2 protein (SGL1 is responsible for the remaining 10%). Cagliflozin reduces the re-absorption of filtered glucose and lowers the renal sugar threshold, thereby increasing urine glucose excretion. This medicine aids diet control and exercise to improve glycemic control in adults with type 2 diabetes.

Invokana® is an oral film tablet with a net content of 100 mg or 300 mg per tablet. The recommended starting dose is 100 mg each time and is taken once a day before the first meal.

 ⇢ Structural formula

 Mechanism  

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Canagliplozin is the first FDA-approved SGLT2 inhibitor for the treatment of type 2 diabetes in adult patients. SGLT is a glucose transporter with two subtypes, SGLT1 and SGLT2, which are distributed in the intestinal mucosa and renal tubules, respectively, and are capable of transporting glucose into the bloodstream. Cagliflozin inhibits SLCT2, so that glucose in the renal tubules cannot be smoothly reabsorbed into the blood and excreted in the urine, thereby lowering blood glucose concentration.

Synthetic route

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 ⇢ Research key data

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Glutamine metabolism and cancer treatment

Author:Si tie

Since the publication of Otto Warburg's groundbreaking research - the aerobic glycolysis theory, glucose metabolism has been a top priority in cancer metabolism research. Studies of other metabolites, such as glutamine, have been shelved until recently in recent decades.

In 1935, Hans Krebs proposed the famous tricarboxylic acid cycle (TCA), pointing out the importance of glutamine metabolism in animals. Subsequent studies have shown that glutamine plays an important role in the growth of normal cells and cancer cells.

In view of the key role played by glutamine in energy production and macromolecular synthesis, related drugs developed for glutamine have great potential for inhibiting tumors. Below we will introduce the physiological effects of glutamine and the clinical progress of inhibitors.

Glutamine metabolism

The high level of glutamine in the blood provides a ready-made carbon and nitrogen source to support the biosynthesis, energy metabolism and homeostasis of cancer cells and promote tumor growth.

Glutamine is transported into cells by the transporter SLC1A5 (solute carrier family 1 neutral amino acid transporter member 5) in the cell.

Under conditions of nutrient deficiency, cancer cells can obtain glutamine by breaking down macromolecules. Over-activation of the oncogene RAS can promote pinocytosis, cancer cells scavenge extracellular proteins, degrade into amino acids including glutamine, and provide nutrients for cancer cells.

Cancer cells absorb large amounts of glucose, but most carbon sources produce lactic acid through aerobic glycolysis rather than in the TCA cycle.

Tumor cells that overactivate the PI3K, Akt, mTOR, KRAS gene or MYC pathway stimulate glutamate metabolism to produce alpha-ketoglutarate by glutamate (GLUD) or transaminase catalysis. Alpha-ketoglutarate enters the tricarboxylic acid (TCA) cycle and provides energy to the cells.

Synthesis of glutamine in nucleic acids, lipids and proteins

Glutamine can be used as a raw material for biosynthesis during cell growth and division. Carbon from glutamine can be used for the synthesis of amino acids and fatty acids, and nitrogen from glutamine acts directly on the biosynthesis of purines and pyrimidines.

Nucleic acid synthesis

Aspartic acid produced by TCA cycle and transamination acts as a key carbon source for the synthesis of purines and pyrimidines. Glutamine-deficient cancer cells are arrested in the cell cycle and cannot be used for nucleic acid synthesis by TCA circulating intermediates such as oxaloacetate. However, supplemental exogenous nucleotides or aspartic acid can alleviate cell cycle arrest caused by glutamine deficiency.

In addition, the glutamine-dependent mTOR signal activates the enzyme carbamyl phosphate synthetase 2, aspartate transferase, and carbamoyl aspartate dehydratase (CAD), which catalyzes the conversion of glutamine-derived nitrogen into pyrimidine. Synthesis of 

precursors.

 Lipid synthesis  

Glutamine is catalyzed by glutaminase (GLS or GLS2) to produce glutamate, which is then catalyzed by glutamate (GLUD) or a transaminase to produce alpha-ketoglutaric acid. Alpha-ketoglutarate produces acetyl-CoA by catalytic reverse, which can be used for direct synthesis of lipids.

Protein synthesis

In addition to the carbon in glutamine for amino acid synthesis, glutamine plays a key role in protein synthesis. Lack of glutamine leads to incorrect protein folding and endoplasmic reticulum stress response.

Glutamine can be synthesized by uridine diphosphate acetylglucosamine (UDP-GlcNAc), a substrate for β-O-acetyltransferase (OGT), which plays an important role in protein folding in the endoplasmic reticulum. The role.

GCN2, a serine threonine kinase, a regulatory domain fragment, is similar to histidine-tRNA synthetase. The combination of glutamine and histidine-tRNA synthetase inhibits the activity of the GCN2 enzyme. The latter played an important role in the overall stress response.

 Glutamine and autophagy 

The relationship between autophagy and glutamine is complex, which is also reflected in the role of autophagy in tumor development.

The role of autophagy in tumors is contradictory: in some cases, it inhibits oxidative stress, leads to chromosomal instability, and inhibits tumor development. Autophagy can also support the survival of cancer cells by promoting pinocytosis and inhibiting stress pathways such as p53.

Glutamine inhibits the activation of GCN2 and comprehensive stress, and ammonia produced from glutamine promotes the development of autophagy in both autocrine and paracrine modes.

ROS can induce autophagy as a stress response, but is neutralized by glutathione and NADPH produced by glutamine metabolism. Glutamine can also indirectly stimulate mTOR, which in turn inhibits autophagy through complex mechanisms.

 Glutamine and ROS 

Reactive oxygen species (ROS)-mediated cell signaling can promote tumor development at a certain physiological level, but when the level is too high, reactive oxygen species can cause great damage to macromolecules in cells. ROS are produced in several ways, in which the mitochondrial electron transport chain produces superoxide (O2−) anions.

However, tumors can control ROS levels through products produced by the glutamine metabolic pathway, preventing high levels of ROS from causing chromosomal instability. The most important way for glutamine to control reactive oxygen species is to synthesize glutathione. Glutathione is a tripeptide that can be used to neutralize peroxyl radicals.

Glutamine can also affect the balance of reactive oxygen species through NADPH. Glutamate produces a series of reactions of malic acid, which is catalyzed by malic enzyme to produce NADPH, which is used to regulate the balance of ROS.

 Clinical application of glutaminase inhibitors 

The dependence of tumor cells on glutamine metabolism makes it a potential anticancer target. Many compounds targeting glutamine metabolism have been the focus of research from initial transport to subsequent conversion to alpha-ketoglutarate.

Although most of them are still in the pre-clinical "tool synthesis" phase or are limited by the toxicity of the compounds, glutaminase (GLS) allosteric inhibitors show great potential in preclinical cancer models, a very active compound, CB-839 has entered clinical trials.

There are two main types of glutaminase in the human body: kidney glutaminase (GLS) and liver glutaminase (GLS2).

Tumor cells over-activated renal glutaminase (GLS), which acts primarily on non-cancer cells to catalyze the metabolism of glutamine.

The pleiotropic effects of glutamine in cell function, such as energy synthesis, macromolecular synthesis, mTOR activation, and reactive oxygen species balance, make GLS inhibitors synergistic in combination therapy.

Inhibition of the glutaminase gene prevents the transition of epithelial cells to mesenchymal cells. This step is a key step in tumor cell invasion and eventual metastasis. Therefore, in the combination therapy of glutamine metabolism inhibition, prevention of metastasis may be a GLS inhibitor. Play an important role in the anti-cancer effect.

Tumor immunization has also become the most promising treatment to date, such as by blocking the immunological checkpoint PD-1 mAb or using engineered chimeric antigen receptor (CAR) T cells.

These methods require immune cells to function in the tumor microenvironment, and metabolic inhibitors in vivo may also affect immune function. Recent studies have shown that immune cells compete with cancer cells for glucose, and glutamine may be a similar mechanism.

In fact, glutamine metabolism plays an important role in the activation of T cells and in the regulation of the transformation of CD4+ T cells into inflammatory subtypes.

Glutamine is critical for the activation of cancer-killing T cells. By blocking the glutamine pathway in cancer cells, the amino acid content of the tumor microenvironment is increased, and the killing effect of immune cells is enhanced.

The combination of GLS inhibitor CB-839 and tumor immunity has also entered clinical phase one.

Tumor microenvironment metabolites and tumor immunity have also become the scent of tumor metabolism, and the recent hot IDO inhibitors are among them.

 Conclusion 

Ninety years ago, Warburg discovered that many animal and human tumors have a very high affinity for glucose, breaking down large amounts of glucose into lactic acid. He also pointed out that cancer is caused by metabolic changes and loss of mitochondrial function.

In addition to the critical role of glucose in the physiological mitochondrial oxidative function of cancer, glutamine plays an important role in tumor cell growth. These arbitrary views have been replaced and improved in the past few decades.

Pleiotropic effects of glutamine in cell function, such as energy synthesis, macromolecular synthesis, mTOR activation, and reactive oxygen species balance.

Tumor cells over-activated renal glutaminase (GLS), whereas normal cells catalyze the metabolism of glutamine as hepatic glutaminase (GLS2). It is possible to selectively develop GLS inhibitors clinically.

Targeting inhibition of some oncogenes makes tumor cells dependent on glutamine, so the combination of targeted inhibitors and glutamine metabolism plays a synthetic lethal effect.

Due to the complexity of the pathogenesis of tumors and the uncertainties of glutamine in human physiological mechanisms, such as 13 years, Professor Shi Yigong of Tsinghua University pointed out that the main role of glutamine metabolism is to produce amines to fight the acidic environment of tumors. Therefore, the combination of GLS inhibitors and other targets has become a trend of development.

 References: 

[1] Altman B J, Stine Z E, Dang C V. From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy [J]. Nature Reviews Cancer, 2016, 16(10): 619.

[2] Mullard A. Cancer metabolism pipelinebreaks new ground[J]. Nature Reviews Drug Discovery, 2016, 15 (11):735.

[3] Huang W, Choi W, Chen Y, et al. A proposedrole for glutamine in cancer cell growth through acid resistance [J]. CellResearch, 2013, 23 (5): 724.

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Two new generations of thrombopoietin receptor agonists are approved

Platelets are colorless cells produced in the bone marrow that help to form blood clots in the vascular system and prevent bleeding. Thrombocytopenia is a condition in which the number of platelets circulating in the blood is lower than normal. Severe or life-threatening bleeding can occur when the patient's platelet count is moderate to severely reduced, especially during invasive surgery. Patients with significant thrombocytopenia typically receive platelet transfusion immediately prior to surgery to increase platelet count. However, platelet transfusion has a risk of infection and other adverse reactions.

Lusutrombopag of Yanyeyi

On July 31, after completing the priority review, the US FDA approved Mulpleta (Lusutrombopag) from Yanyeyi, a daily small-dose thrombopoietin (TPO) receptor agonist for oral treatment. Thrombocytopenia in adults with chronic liver disease (CLD) undergoing surgery.

Thrombocytopenia is often observed in patients with CLD, and studies have shown that it occurs in 78% of patients with cirrhosis. The thrombocytopenia associated with CLD is defined as a platelet count of less than 150,000 per microliter. CLD thrombocytopenia increases the risk of bleeding and requires repeated platelet transfusions, thereby increasing outpatient visits and hospitalizations. Patients with CLD with thrombocytopenia have a three-fold higher annual medical cost than patients with CLD without thrombocytopenia. When the platelet count is less than 50,000/μl, surgery or traumatic bleeding is exacerbated, and routine diagnostic procedures and patient care are significantly complicated. Therefore, there is an urgent need for new treatment options in this field. At the same time, adult patients with chronic liver disease often need surgery for various reasons, and can provide this new oral treatment to patients without relying on platelet transfusion.

Mulpleta (Lusutrombopag) interacts with the transmembrane domain of human TPO receptor expressed on megakaryocytes to induce proliferation and differentiation of megakaryocyte progenitor cells from hematopoietic stem cells and megakaryocytes.

The FDA approved Mulpleta based on two Phase III clinical trials (L-PLUS 1 and L-PLUS 2), and Mulletta met both primary and secondary endpoints with statistically significant results.

In September 2015, Mullleta was approved by the Japanese Ministry of Health, Labor and Welfare to improve CLD-related thrombocytopenia in patients undergoing selective invasive surgery. The European Medicines Agency has also verified the application of the lusutrombopag standard marketing authorization application for Yan Yeyi, which is expected to be approved in the first half of 2019.

In the United States, Mulpleta is expected to be available in early September 2018.

Avatrombopa of AkaRx

On May 21, Dovaex (Avatrombopag) of Dova's AkaRx company received FDA approval for the treatment of chronic liver disease in adults undergoing dental or other surgery for low thrombocytopenia. It is the first drug approved by the FDA for this purpose.

The safety and efficacy of Doptelet was studied in two trials (ADAPT-1 and ADAPT-2) involving 435 patients with chronic liver disease and severe thrombocytopenia who plan to receive a platelet transfusion that usually requires surgery. Two dose levels of Doptelet administered orally within 5 days compared to placebo (untreated) were tested. The results of the trial showed that for the two dose levels of Doptelet, the platelet count was increased in a higher proportion of patients, and platelet transfusion or any salvage therapy was not required on the day of surgery and within 7 days after surgery.

Received market attention

Both Mulpleta and Doptelet have an urgent market demand and are receiving attention.

Mulpleta of Yanyeyi and Doptelet of AkaRx are very similar in terms of safety, efficacy and ease of administration. Yan Yeyi won the FDA's approval of Mullleta, but AkaRx's Doptelet was approved in the US two months earlier than Mullleta, and it is foreseeable that the competition between the two will be fierce.

Some analysts said that the degree of competition will depend on market access and pricing strategies. Mulpleta (lusutrombopag) of Yanyeyi has been approved in Japan and has two clinical studies to prove its case. In both trials, 78% and 65% of patients did not require platelet transfusion before surgery, compared with 13% and 29% of the placebo group.

Compared with Doptelet, although Mulpleta has a lower clinical response rate, Leerink analyst Geoffrey Porges pointed out that the limit of Yan Yeyi is strict. Therefore, he believes that the two drugs "do not seem to have a difference in efficacy."

Both drugs have their own advantages in terms of ease of administration. Unlike the complex dosing regimen used in some clinical trials, Mullletta's instructions indicate that it uses a fixed dose of 7 days, which is longer than the standard required by Doptelet for 5 days.

However, as Evercore ISI analysts Jon Miller and Umer Raffat point out, Mullleta can start 8 to 14 days before scheduled surgery, while Doptelet's window is relatively narrow in 10 to 13 days. Mulpleta's wider time window may make the surgery plan easier to arrange. In addition, the patient can be dosed close to the date of the scheduled surgery, and if the cytopenia problem occurs during this process, the administration is easier.

Because the characteristics of the two drugs are very similar, both the Leerink and Evercore teams believe that the pricing strategy will be a key factor in the gap between the two drugs.

Yan Yeyi has not announced its price or release schedule. Dova's AkaRx has announced that Doptelet's 40 mg tablet is priced at $9,000 and 60 mg is $13,500, which is higher than Leerink's previous forecast of $6,000. Some analysts expressed concerns about their high prices. It is difficult to predict how responders (medical insurance agencies) respond to this pricing policy, and in many cases, the cost is even higher than surgery. To ensure successful sales, both Dova and Yan Yeyi have developed a reimbursement support program and set up a team with experience in sales of liver disease.

There is also an urgent need for such drugs in the country. It is known that on March 19 this year, Fosun Pharma and AkaRx reached an agreement on Avatrombopag to obtain an exclusive license for the development and sale of the drug in mainland China and Hong Kong. Under the agreement, Fosun Pharma will assist AkaRx in developing Avatrombopag in China and Hong Kong to treat thrombocytopenia in patients with chronic liver disease and will support its development for other indications. Avatrombopag has been approved for chronic liver disease-related thrombocytopenia, and it is also undergoing chemotherapy-induced thrombocytopenia and chronic idiopathic thrombocytopenic purpura. In addition to being approved for chronic liver disease thrombocytopenia, Mulpleta is also being used clinically for immune thrombocytopenia.

According to the survey, the basic patent of Avattombopag will expire in 2023. The Lusutrombopag patent claimed by Yanyeyi Company is more complicated, and it receives multiple patent protections, and it will take some time to expire.

Acotiamide HydrochlorideHydrate/Acofide®

Acotiamide HydrochlorideHydrate/Acofide®

Basic Information

Acotamine hydrochloride was jointly developed by Japan Zeria and Astellas. It was approved by the Japanese Pharmaceutical Medical Device Integration Agency (PMDA) on March 25, 2013, and was jointly produced by Zeria and Anstel. It is marketed in Japan under the trade name Acofide®.

Acotamine hydrochloride is a novel selective acetylcholinesterase (AChE) inhibitor. Acetylcholine is an important neurotransmitter that regulates gastrointestinal motility. Acotamine improves the symptoms of functional dyspepsia by inhibiting the degradation of acetylcholine, improving impaired gastric motility and delayed gastric emptying. This medicine is suitable for improving the feeling of postprandial bloating caused by functional dyspepsia, feeling of fullness in the upper abdomen and premature sensation.

Acofide® is an oral film-coated tablet containing 100 mg of acotamine hydrochloride. The recommended dose is 100 mg per adult, 3 times a day, before meals.

Structural formula

Mechanism

synthetic route

Research key data

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GMP Manufacturer， Efinaconazole (164650-44-6)and intermediates

Efinaconazole

API Name: Efinaconazole 

CAS#: 164650-44-6 

Formula: C18H22F2N4O 

Exact Mass: 348.1762 

Molecular Weight: 348.39 

Elemental Analysis: C, 62.05; H, 6.36; F, 10.91; N, 16.08; O, 4.59

Structural formula:

We have more than2.5kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

 Efinaconazole  intermediates

1.Name:(2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butane-2,3-diol

CAS:133775-25-4

Structural formula:

We have more than1.8kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

2.Name:QANJLSHZDUOBBP-QPUJVOFHSA-N

CAS:127000-90-2 

Structural formula:

We have more than2.3kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

3.Name:4-methylenepiperidine hydrochloride; 4-methylidenepiperidine hydrochloride

CAS:144230-50-2

Structural formula:

We have more than1.7kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Contact information：

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.

 Efinaconazole  impurities

 Efinaconazole Impurity 1

 Efinaconazole Impurity 2

 Efinaconazole Impurity 3

 Efinaconazole Impurity 4

 Efinaconazole Impurity 5

 Efinaconazole Impurity 6

Reference

1: Pollak RA. Efinaconazole topical solution, 10% the development of a new topical treatment for toenail onychomycosis. J Am Podiatr Med Assoc. 2014 Nov;104(6):568-73. doi: 10.7547/8750-7315-104.6.568. PubMed PMID: 25514267.

2: Tosti A, Elewski BE. Treatment of onychomycosis with efinaconazole 10% topical solution and quality of life. J Clin Aesthet Dermatol. 2014 Nov;7(11):25-30. PubMed PMID: 25489379; PubMed Central PMCID: PMC4255695.

3: Gupta AK, Simpson FC, Abramovits W, Scheinfeld N. Efinaconazole 10% nail solution: a post-FDA approval update. Skinmed. 2014 Jul-Aug;12(4):235-7. PubMed PMID: 25335353.

4: Zeichner JA, Stein Gold L, Korotzer A. Penetration of ((14)C)-Efinaconazole Topical Solution, 10%, Does Not Appear to be Influenced by Nail Polish. J Clin Aesthet Dermatol. 2014 Sep;7(9):34-6. PubMed PMID: 25276275; PubMed Central PMCID: PMC4174918.

5: Joseph WS, Vlahovic TC, Pillai R, Olin JT. Efinaconazole 10% solution in the treatment of onychomycosis of the toenails. J Am Podiatr Med Assoc. 2014 Sep-Oct;104(5):479-85. doi: 10.7547/0003-0538-104.5.479. PubMed PMID: 25275736.

6: Efinaconazole topical solution (Jublia) for onychomycosis. Med Lett Drugs Ther. 2014 Sep 15;56(1451):88-9. PubMed PMID: 25211303.

7: Jo W, Glynn M, Nejishima H, Sanada H, Minowa K, Calvarese B, Senda H, Pillai R, Mutter L. Nonclinical safety assessment of Efinaconazole Solution (10%) for onychomycosis treatment. Regul Toxicol Pharmacol. 2014 Oct;70(1):242-53. doi: 10.1016/j.yrtph.2014.07.012. Epub 2014 Jul 16. PubMed PMID: 25038564.

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9: Iwata A, Watanabe Y, Kumagai N, Katafuchi-Nagashima M, Sugiura K, Pillai R, Tatsumi Y. In vitro and in vivo assessment of dermatophyte acquired resistance to efinaconazole, a novel triazole antifungal. Antimicrob Agents Chemother. 2014 Aug;58(8):4920-2. doi: 10.1128/AAC.02703-13. Epub 2014 May 27. PubMed PMID: 24867968; PubMed Central PMCID: PMC4136074.

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