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2018年8月30日星期四

Cobicistat/Tybost®

⇝ Basic Information

Developed by Gilead, Cobicistat was approved by the European Medicines Agency (EMA) on September 19, 2013 under the trade name Tybost®; after September 24, 2014, the US Food and Drug Administration (FDA) Approved for sale, the trade name is Stribild®, which is marketed by Gilead in the US and Europe.

Cobicistat is a cytochrome P4503A inhibitor. Cobicistat is similar in structure to ritonavir (Nove) and inhibits the activity of hepatic enzymes involved in the metabolism of other anti-HIV drugs, especially the inhibition of the metabolism of levigovir (HIV integrase inhibitor) by hepatic enzymes. When used in combination with Cobicistat, entegitide achieves higher blood levels at lower doses, thereby increasing viral inhibition and reducing side effects. Unlike ritonavir, Cobicistat is the only approved cocktail therapy (HAART) drug enhancer that does not itself have anti-HIV activity.

Tybost® is an oral film-coated tablet containing 150 mg of Cobicistat per tablet. The recommended starting dose is: combined with emtricitabine or darunavir, 150mg each time, once a day, with meals.

⇝ Structural formula

 


  ⇝ Mechanism


 Cobicistat (GS-9350) is a potent CYP3A selective inhibitor with an IC50 of 30 - 285 nM. Cobicistat (GS-9350) is a potent inhibitor of the potent human cytochrome P450 3A (CYP3A) enzyme.

⇝Synthetic route



















Research key data

This article is reproduced from:https://news.pharmacodia.com/news/html/info/info-detail.html?id=29609

The first immunotherapy "Shen medicine" went on the market Pharmaceutical giants set off time war

Author: Liang Jialin


A new generation of "magic drugs" - immunological tumor PD-1 treatment drugs officially listed in China this week. Pharmaceutical giants have to set off a "war of time" in a very limited market monopoly, grab pricing benchmarks, grab market capacity, and grab sales channels.

From August 28th, the first PD-1 anticancer drug Opdivo (Chinese name “Oddivo”, commonly known as O medicine), which was approved for listing in China, was officially launched in more than 50 cities in China. On the 29th, Hubei, Anhui, Henan, Shanghai and other places have successively issued the first prescription for local immunotherapy. It is rumored in the medical circle that the first-day sales of O-pharmaceuticals exceeded 100 million.

Although the authoritative source of this data is not testable, the head of the relevant department of Bristol-Myers Squibb (BMS) China has replied to the health point that it will not be commented. However, it is undeniable that as the anti-cancer "magic medicine" that pioneered the revolutionary treatment of cancer treatment, even if the patient still bears the expenses at his own expense, the demand for clinical outbreak is obvious. And the previous "Shenzhen" Gleevec has set off a series of storms such as overseas drug purchases and Lu Yong's arrest. This time, the O-pharmaceutical pricing and circulation strategy for landing in China will not give the drug gods overseas purchases. Opportunity. According to Liu Qian, a medical marketing expert, BMS has set the price of medicines to be only two-thirds of Hong Kong, China, and far below the US domestic price. Goldman Sachs Consulting even predicts that this will give birth to a wave of “medical tourism” opportunities for overseas patients to come to China for immunotherapy.

However, medical industry experts interviewed by health points agreed that as the competing products in the same industry followed the listing, it is assumed that the approval efficiency of expanding the indications remains at the level of “Bijingquan period”, and O medicine is the first immunotherapeutic drug in China. The market monopolization period is less than half a year. In response, BMS companies need to speed up the approval of O-drugs for indications other than non-small cell lung cancer; on the other hand, they need to speed up the layout in DTP pharmacies and medical insurance access. At the time of writing, the person in charge of the relevant department of Bristol-Myers Squibb China said that it would not comment.

For cancer patients, more immune tumor (I-O) treatments are both a puzzle and a gospel. On the one hand, this increases the decision-making cost of patients choosing different drugs. The key point is which patients who are more precise in patient “stratification” and achieve precise personalized treatment, thus improving the response rate of immunotherapy only 20%. On the other hand, this is conducive to reducing the cost of purchasing drugs for patients. The drugs that are listed on the market need to comply with the relatively low price benchmark established by O medicine, and achieve competitive in the process of access to basic medical insurance and commercial insurance. Sub-price reduction.

Pricing: lower than expected, expected to cut prices twice

On June 15, the State Food and Drug Administration (CNDA) announced that O medicine has become the first monoclonal antibody to target PD-1 in China. Yin Wei, CEO of Huada Gene, commented in a circle of friends that if O medicine can set the price at one-tenth of the US, that is, 100,000 yuan/year, the national basic medical insurance should be very happy to cover, but the possibility is very low. At that time, he predicted that the price of O medicine in China was between RMB 400,000 and RMB 600,000.

Yin Wei only guessed half of it, O medicine did not include health insurance for the first time, but the price is still lower than market expectations. On August 20th, BMS announced the pricing system, which allowed an investor in Yikai Capital to call out “how many (the pharmaceutical companies) comrades’ model assumptions should be torn off and rearranged”. The suggested retail price of O medicine is set at 100mg/10ml 9260 yuan; 40mg/10ml 4591 yuan. Patients with different body weights have different amounts of guidance. For example, in a 50 kg patient, intravenous injection is performed once every two weeks, and one 100 mg/10 ml and two 40 mg/10 ml are used at a time.

Therefore, the industry ridiculed "O medicine theory to sell". Some people have calculated it by themselves. According to BMS's recommendation, the monthly medication cost for a 50kg body weight patient is about 27,000 yuan, while the 80kg body weight patient's medication cost is about 46,000 yuan per month.

Before announcing the appointment of AstraZeneca as China's vice president, Liu Qian, a pharmaceutical marketing expert, commented on the O-pharmaceutical pricing strategy, saying that BMS's suggested retail price is almost one-third cheaper than Hong Kong. This shows that the manufacturer responded to the government's call and complied with the trend since the performance of "I am not a drug god", and set a global "floor price". A monoclonal antibody product that requires a cold chain is even lower in price than a small molecule targeted drug, and it needs to be in the top three in the next immune-tumor (I-O) therapeutic drug war.

Liu Qian even believes that the rhythm of several companies listed and approved, "deliberately avoided" the anti-cancer drug medical insurance drug access negotiations organized by the National Medical Insurance Bureau. A number of pharmaceutical industry experts told health points that O medicine is currently in the market exclusive period of the immune tumor (IO) treatment competition. Instead of accepting medical insurance negotiations to passively reduce prices, it is better to take the initiative to control the price reduction rhythm, so let the published price time dragged through June 31 Japan. The deadline for the round of medical insurance price negotiations is a wise choice.

Idea Di CEO Gong Zhaolong told the health point that the price of O drug is the first time in the world that the hot-selling Chinese imported drug is far lower than the developed countries in Europe and America, reflecting the efforts of the government, especially the National Health Insurance Bureau, to lower the price of drugs. Play the effect. BMS has received very good positive feedback from the “price-for-price” strategy. The first day sales were very large, and some regions even experienced short supply, which made the global headquarters more motivated to distribute more drugs to China and put more marketing. Resources to meet the needs of Chinese cancer patients.


Gong Zhaolong believes that the price benchmark is significantly lower than expected, which will help to quickly seize patients in the market exclusive period. Because patients with advanced and metastatic non-small cell lung cancer use O drugs, they will not easily switch to other immunotherapeutics, and BMS will join the relevant agencies to launch charitable drug-donating programs, which will further improve patient loyalty.

A number of interviewed experts said that, in view of the surrounding market, as the patent period expires, the competitive products of the same indication are listed, in order to maintain a high market share, the price of O medicine can only choose to cut prices twice. Take the developed country market in Japan as an example. Since the 100 mg bottle was launched in 2014, the price of O medicine has dropped from 730,000 yen just listed to 278,000 yen in March 2018. It is expected to fall to 17.4 in November. Ten thousand yen.

Another way to maintain a high enough market share is to access the commercial insurance system. The PD-1 immunotherapy drug listed immediately after the O drug is the pembrolizumab monoclonal antibody (commonly known as K drug) of Merck (MSD). The market is expected to be available in September. Merck (MSD) has revealed that K medicine has joined China Ping An Insurance's first catalogue of new drug-preserving tumors in China - "Safety Insurance New Drugs Catalogue". Of course, the amount of insurance for commercial insurance is much higher than that of basic medical insurance.

As a former senior reviewer of the US Food and Drug Administration (FDA), Gong Zhaolong believes that the first indication for K drug in China is systemic treatment of advanced melanoma, unlike advanced and metastatic non-small cells of O drug. Lung cancer, therefore, the introduction of super-indications in specialized hospitals such as chest hospitals and pulmonary hospitals in the early stage will be hindered. However, Gong Zhaolong believes that K-medical non-small cell lung cancer and other large indications are also accelerating the listing, and the National Bureau has launched the acceptance of overseas clinical trial data as a basis for reporting the policy of supporting domestic listing. O-drug may only be in the market for large indications. Half a year. Gong Zhaolong compared FDA experience, the fastest time for FDA to expand the indication is 4 working days.

At the same time, domestic PD-1 immunotherapy drugs are also on the way to the road. As of August this year, three Chinese pharmaceutical companies have submitted new drug listing applications to the State Food and Drug Administration (CFDA), all of which are immunotherapeutic drugs of the same type as O drugs. They are: Shanghai Junshi (indications: melanoma), Cinda (Hodgkin's lymphoma), and Hengrui Medicine (Hodgkin's lymphoma). Cinda Biology and Baekje Shenzhou have entered the clinical trial phase 3 with immunotherapy drugs for non-small cell lung cancer.

Market: Opportunities and risks of over-indications

Li Dinggang, executive director of Lu Daopei Blood Hospital, said that with the listing of O medicine in mainland China, “the emergence and clinical application of an innovative drug will definitely bring about an innovative diagnosis and treatment system, especially in the era of biological immunotherapy.” Li Dinggang said that when medicine is available, doctors are extremely important factors in how to diagnose and formulate medication regimens. Just as China originally had its own aircraft carrier, but lacked the carrier commander. For most oncologists in mainland China (inland), PD-1 is a new drug, with insufficient experience in drug administration, and has not dealt with the experience of related side reactions brought about by the use of PD-1.

The doctor's prescription right not only determines the quality of life of the patient, but also determines the market size of the O drug. At present, O-medicine approved indications in mainland China specifically refer to advanced or metastatic non-small cell lung cancer (NSCLC) that meet specific conditions. Chen Xiaodong, director of the Propaganda Department of the Chinese Affairs Department of the US-China Medicine Association, said that in foreign countries, O-drugs have been approved for a variety of indications, covering melanoma, non-small cell lung cancer, kidney cancer, Hodgkin's lymphoma, head and neck cancer, bladder cancer, Colorectal cancer, liver cancer, gastric cancer and other tumors.

In February 2018, the latest national cancer statistics released by the National Cancer Center showed that in 2014, the number of new cases of malignant tumors in the country was estimated to be 3.804 million, and lung cancer ranked first in the national cancer, with an annual incidence of about 781,000. Gong Zhaolong believes that a large number of patients with failed first-line treatment will receive second-line treatment, and the market demand is huge.

To expand market capacity, expanding the scope of indications is a shortcut. An insider of BMS revealed that the company was the first in China to complete the first PD-1/PD-L1 clinical study, which is unparalleled in scale. Gong Zhaolong said that although pharmaceutical companies are not allowed to market for hyperindications, patients may still be over-indications.

It is important to emphasize that patients with over-indication medications will be at their own risk. According to media reports, after Hong Kong martial arts star Ji Chunhua was diagnosed with advanced lung cancer, a large-scale top three hospital in Hangzhou was confirmed to have been unable to undergo surgery, chemotherapy, radiotherapy and other treatments. After learning about the illness, Hong Kong friends specially purchased PD-1 from Hong Kong. The immunotherapeutic drug (Kreida, commonly known as K drug) is for his use. However, the treatment of two courses, the effect is not good, unfortunately passed away in July this year. Ding Lihua, CEO of Zero Technology, told the health point that one of the deaths of Ji Chunhua may be the acute multiple organ failure caused by the drug. However, for second-line treatment, there is no medicine to save, patients and their families are willing to "dead horses to live horse doctors."

Hyperindication medications also bring more uncertainty to oncologists' clinical decisions. Ji Dongmei, deputy director of Department of Oncology, Fudan University Cancer Hospital, said in an interview with R&D guests that although some indications are already undergoing clinical research, such as soft tissue sarcoma, PD-1 monoclonal antibody treatment is used in these patients with hyperindications. At the same time, it is still necessary to be cautious and the treatment effect may be less than expected. Tumors, such as malignant melanoma and recurrent Hodgkin's lymphoma, which have proven to be more effective, are more likely to try PD-1 monoclonal antibody therapy.

Channel: DTP pharmacy into the main channel of the initial stage of listing

At 4 o'clock on the morning of August 29, the first batch of O medicine arrived in Sinopharm Henan Company. When a child was finished, the medicine was put on the shelves, and the first bill was completed at 7:57. At 8:33 in the morning, Zhengzhou Pharmacy received the drug. Henan's first prescription.

Similar scenes have occurred in Wuhan, Hefei and Changsha.

On the first day of the O-pharmaceutical market, the performance of the DTP pharmacy system attracted industry attention. This is the treatment that Iressa, Gleevec and other "precursor gods" do not have. Compared with public hospitals such as Shanghai Chest Hospital, DTP pharmacies not only achieved the first time distribution, but also allowed cross-city distribution within the region. Zhang Xiaodong, CEO of Magnesium Health, which provides services for many DTP pharmacies in China, expects that DTP pharmacies will increasingly become the mainstream channel for special drug sales. The DTP channel of a certain three-generation targeted drug in China accounts for 90% of the time. It is expected to be listed on O-drug. In the early days, the proportion of DTP channels will be higher.

Ding Lihua revealed that the efficiency of drug administration in public hospitals is affected by the proportion of drugs formulated by the medical administrative department (the proportion of drug revenues to the total income of hospitals - editor's note), and is also affected by the total amount of medical insurance formulated by the medical insurance administrative department. Once the proportion of medicines and the total amount of medical insurance are approached or exceeded, the motivation for public hospitals to purchase high-value drugs will be greatly reduced. Coupled with the implementation of the elimination of drug additions throughout the country, public hospitals do not make money on drugs and drugs. In contrast, DTP pharmacies are not subject to these rules, which has led to the emergence of a prescription outflow market – patients prescribing in public hospitals and purchasing medicines at DTP pharmacies (to take medicine at the store or to deliver medicines to the door).

As early as June 22, Bristol-Myers Squibb (BMS) signed a strategic cooperation agreement with Shanghai Pharmaceuticals around O-Pharma. Although the signing parties did not disclose the details of the agreement, according to the information provided by Shanghai Pharmaceutical Health, on the first day of the listing of Opharmaceuticals, Shanghai Pharmaceutical Holdings fully accelerated and successfully completed the nationwide initial sale and expedited distribution to all parts of the country. On August 28th, as the DTP brand of Shangpin Yunjian, which is owned by Shanghai Pharmaceutical Holdings, “Yi Pharmaceutical·Pharmacy” started the sale of O medicine in the country, and provided services such as drug consultation, drug delivery, health management, and patient education. Up to now, “Yi Pharmaceutical·Pharmacy” covers 6 DTP pharmacies in 6 cities including Shanghai, Hangzhou, Changzhou, Nantong, Wuxi and Xuzhou.

On the same day, on the afternoon of the 28th, the neighboring customers and wisdom pharmacy under Zero Technology were the only DTP pharmacies in Heilongjiang Province, and completed 5 patients' drug purchase services within 4 hours. According to the information provided by the company, patients can use the DTP pharmacy to use pharmacy services, such as the whole process of adverse reactions during drug use, consultation on all aspects of drug use, and application of patient management system with independent intellectual property rights. Drug patients were followed up by medication.

In November 2017, under the guidance of the National Population and Health Promotion Committee of the National Health and Family Planning Commission, the research report on “China Tumor Patient Service Upgrade” jointly issued by Caixin Health Point and the China Anti-Cancer Association Rehabilitation Association showed that patients with cancer were diagnosed and treated. In the link, 52% of the respondents communicated with the doctor in charge for less than 10 minutes each time, and 70% of the respondents never received an invitation to the disease lecture from the hospital. For most cancers, including breast cancer, treatment technology advancement has achieved "long survival," which means that the long-term management of "cancer chronic disease" patients in medical institutions has proliferated, and hospitals cannot fully meet the needs of post-hospital follow-up.

In order to meet the above-mentioned patient needs, in addition to the introduction of medical social workers to participate in health science, the introduction of pharmacists to provide reasonable medication counseling services, also requires high-level social medical institutions to provide, such as some high-end private hospitals, DTP pharmacies, to provide health education for patients. Services such as disease management, to make up for the gap in demand left by public hospitals.

The experts interviewed expect that O medicine as a prescription drug needs to be prescribed under the guidance of a doctor. If the state encourages the DTP pharmacy policy to fall, the sales of DTP channels will be greatly increased. Since O medicine is an injection, intravenous administration needs to be completed in a hospital, and it is necessary to monitor adverse reactions after administration. Relatively speaking, large-scale hospital medication is safer. With the accumulation of medication experience, small hospitals, clinics and even DTP pharmacies that meet the treatment conditions will appear, but it is unrealistic to release them in the short term. A market expert who asked not to be named also reminded that it will take a long time for China to achieve a true “medical separation”. Although the president of a public hospital knows that selling medicine does not make money, the purchase of medicine is still a big power in his own hands.

Due to well-known reasons, some public hospitals with unobstructed access to medicines and adequate supply of medicines may use the safety of medication as an excuse to ban the use of purchased medicines (including DTP pharmacies) in our hospital. To this end, Zhang Xiaodong said that Magnesium Health has set up an external cooperation network. If some patients who purchase O medicine through DTP pharmacy are refused to be consulted in public hospitals, they can go to Shanghai Jiahui International Hospital for immunotherapy. However, because foreign-funded hospitals do not include basic medical insurance, patients are required to pay higher medical service fees.

But Ding Lihua believes that public hospitals and DTP pharmacies are not completely competitive. The advantage of DTP pharmacy lies in its differentiated development from hospitals. For high-value special medicines such as O medicine, if there are many DTP pharmacies in the sales system, why should the hospital divert prescriptions to a DTP pharmacy? Ding Lihua said: First, we must look at the above-mentioned value-added services provided by pharmacies. Second, we must see whether the Internet hospital can clearly price the price, and provide doctors with out-of-hospital prescriptions to provide legal pharmacy service fee income. Third, look at the promotion effect of the drug market and sales department; It is to see if the patient can directly ask the doctor to prescribe the prescription for medicine. For example, the DTP pharmacy will give the patient the profit of the channel difference, and the patient can enjoy the promotion period reward in the DTP pharmacy.



This article is reproduced from:https://news.pharmacodia.com/news/html/info/info-detail.html?id=29646

2018年8月29日星期三

Cetilistat/Oblean®

↬ Basic Information

Cetilistat was jointly developed by Norgine and Takeda and was approved by the Japan Pharmaceutical and Medical Devices Integration Agency (PMDA) on September 20, 2013. It is marketed by Takeda in Japan under the trade name Oblean®. .

Celeste is a pancreatic lipase inhibitor that breaks down triglycerides in the intestines. Both Sylvester and the previous orlistat act by inhibiting pancreatic lipase. Without pancreatic lipase, triglycerides obtained from the diet are directly excreted because they cannot be hydrolyzed into absorbable free fatty acids. The drug is indicated for the treatment of obesity complications, limited to patients with both type 2 diabetes and dyslipidemia, and with a BMI greater than 25 kg/m2 despite undergoing controlled diet and exercise therapy.

Oblean® is an oral tablet containing 120 mg of celestatin per tablet. The recommended dose is 120mg each time, 3 times a day, and taken immediately after a meal.

↬ Structural formula



↬ Mechanism



Is a long-acting and potent specific gastrointestinal lipase inhibitor that inactivates enzymes by forming covalent bonds with the active serine sites of gastric and intestinal lumen gastric lipase and pancreatic lipase. In order to exert a therapeutic effect, the inactivated enzyme cannot hydrolyze the fat in the food, mainly triglyceride, into an absorbable free fatty acid and a monoacylglycerol. Undigested triglycerides are not absorbed by the body, reducing calorie intake and controlling body weight

↬ Synthetic route


↬ Research key data




This article is transferred from:https://news.pharmacodia.com/news/html/info/info-detail.html?id=29523

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.

This article is transferred from:https://news.pharmacodia.com/news/html/info/info-detail.html?id=29536

2018年8月28日星期二

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  

                 ⇲
                     ⇲
                         ⇲



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




This article is reproduced from:https://news.pharmacodia.com/news/html/info/info-detail.html?id=29470







2018年8月27日星期一

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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