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

The above content is transferred from https://news.pharmacodia.com/news/html/info/info-detail.html?id=28877

US study found that cannabidiol can reduce the risk of drug-resistant seizures

According to a report by the US “Qiaoqiao.com” on August 14, researchers at the University of Alabama at Birmingham (UAB) found that a drug ingredient extracted from cannabis, Cannabidiol (also known as CBD), Treatment of drug-resistant epilepsy is effective. The study was published in the journal Epilepsy and Behavior.

According to the United Press International, the researchers pointed out in the report that CBD can effectively reduce the number of episodes of patients with epilepsy who are resistant to traditional therapy.

The US Food and Drug Administration (FDA) approved "Epidiolex" in June for the treatment of two rare drug-resistant epilepsy. This is also the first time the FDA has approved the use of purified drugs extracted from cannabis. The drug contains only traces of tetrahydrocannabinol (THC), which is also the toxic component of hallucinogenic addiction contained in cannabis.

Dr. Martina Bebin, a researcher and professor of neurology at UAB Medical School, said that they registered all patients with various treatment-resistant epilepsy in the study. The results showed that CBD may be resistant to the whole. Epilepsy is effective within the scope of the disease.

The study began in 2015 when the Alabama legislature approved the Carly's Law, which authorizes UAB and the Alabama Children's Epilepsy Center to study with cannabinol. The study participants included 132 patients, including 72 children and 60 adults.

During the first 12 weeks of the study, the frequency of participants' episodes decreased from 144 to 52 episodes per two weeks and remained stable throughout the 48-week study.

"In the study, most patients experienced a significant reduction in seizures," Beckin said. "There was almost a two-third reduction in the overall study population, and some patients had even more frequent seizures. At the same time, the overall seizures of participants were severe. The degree has also been greatly reduced."

Dr. Jerzy Szaflarski, director of the UCSB epilepsy center, noted that the results of the study were clinically significant and that most participants showed an improvement of 50% to 60%, and there were few participants in the treatment process. side effect.

MOTIF skin infection drug ICLAPRIM received FDA priority review

On June 20th, Motif Bio, an antibiotic new drug research and development company, announced that it has submitted a new drug marketing application (NDA) for the drug iclaprim to the US FDA. On August 14, the company announced that the US FDA has accepted NDA from iclaprim, a targeted drug for Gram-positive bacteria intended to treat acute bacterial skin and skin structure infections (ABSSSI). This decision means that the FDA has determined the completeness of the application and is sufficient for a substantive review. For the NDA application, the FDAFA date determined by the US FDA is February 13, 2019.

Motif Bio CEO Graham Lumsden said: "The FDA's recognition of NDA is an important milestone for us. I believe that if the drug is approved, iclaprim may become an important new treatment for patients with severe skin infections. We look forward to working closely with the FDA. And strive to pass the review process in order to bring better therapeutic options to patients as soon as possible."

In the United States, there are more than 3.6 million patients hospitalized for ABSSSI each year. It is estimated that up to 26% of hospitalized ABSSSI patients have kidney damage. Hospitalized patients with obesity, diabetes, and/or renal dysfunction are particularly susceptible to kidney damage caused by standard therapy vancomycin-related drugs. Many standard Gram-positive antibiotics are not suitable for treating such hospitalized ABSSSI patients due to efficacy and/or safety issues.

The NDA included two clinical trials of REVIVE-1 and REVIVE-2 for assessing the efficacy of ABSSSI patients. In both trials, iclaprim reached the primary end point of study compared to the current standard of care, vancomycin, which was the case for patients with intention-to-treat (ITT) who started taking iclaprim for 48-72 hours at an early time point. Effect (NI) (10% margin) results. In the end point of the test, the drug reached the NI (10% margin) 7-14 days after the ISTlaprim was discontinued in ITT patients.

Iclaprim is certified by the US FDA for Qualified Infectious Disease Products (QIDP). If the drug is approved for marketing as a new chemical entity in the form of QIDP, it will be eligible for 10 years of market exclusive treatment in the United States from the date of approval, under the US Generating Antibiotic Incentives Now Act.

                      Iclaprim molecular structure (from Wikipedia)

Iclaprim is a novel antibiotic that has antibiotics that target Gram-positive bacteria. Unlike commonly used broad-spectrum antibiotics, this “precise medical approach” complies with antibiotic management principles and can reduce inappropriate use of broad-spectrum products to avoid accumulation of resistance and reduce the impact on the patient's microbiota. So far, the drug has been studied in more than 1,400 patients and healthy volunteers. Clinical and microbiological data indicate that Iclaprim has a targeted Gram-positive activity profile, low drug resistance propensity and good tolerance.

Inflammatory Bowel Disease: Progress in Clinical Small Molecule Drug Research

  

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease. It has a high incidence in western developed countries. The incidence of IBD in China has been increasing year by year, and it has become a common disease in the digestive system. IBD mainly includes Ulcerative colitis (UC) and Crohn's disease (CD), and its pathogenesis is still unclear. Current research is generally considered to be related to genetic, environmental and immune abnormalities: Genetic and environmental factors induce activation of the intestinal immune system, triggering an excessive inflammatory response and continuing to progress, thereby destroying the intestinal wall and producing clinical signs of IBD. So far, there is no drug to completely cure IBD. Monoclonal antibody is currently the most effective drug for relieving IBD symptoms. However, all drugs need to be administered by injection. Patients have poor compliance, high cost of treatment, and long-term use is prone to drug resistance. Adverse reactions, therefore, small molecule drugs for IBD have become a research hotspot in this field in recent years. The IBD drugs in clinical research are reviewed.

1.S1P receptor modulator

Phosphorylation of intracellular sphingosine forms sphingosine-1-phosphate (S1P), which is controlled by two sphingosine kinases, SK1 and SK2, which produce S1P that binds to the S1P receptor subtype (S1PR1 to S1PR5) Prevent lymphocytes from entering the bloodstream, thereby reducing the inflammatory response. Fingolimod is a sphingosine analogue that is activated by SK2 phosphorylation to form activated phosphorylated fingolimod, an agonist of S1PRs (except S1PR2), capable of inducing immunosuppression, and has been approved for multiple A drug for sclerosis (MS), but it is found to have a risk of heart rate mitigation in clinical use, possibly related to activation of S1PR1 and activation of other S1P receptors (especially S1PR3). Fingolimod has a unique pharmacokinetic property, its absorption is slow, peak plasma concentration is reached 8-36 h after oral administration, and it has a high volume of distribution and half-life in vivo (about 108 h). Fingolimod's dosing regimen is once a day, and it takes about 4 weeks to reach a steady-state plasma concentration, which increases the concentration of the drug in the tissue by 11-19 times compared to the first dose. In terms of IBD drug development, fingolimod showed good efficacy in a variety of mouse models of IBD. Structural modification of the fatty chain of fingolimod, replacing the fatty chain fragment with an aromatic ring to obtain KRP203 (Kyorin Pharmaceutical), which acts in a similar manner to fingolimod, in the case of sodium dextran sulfate (DSS) and IL-10 The gene knockout IBD mouse model showed better efficacy. At present, KRP203 has entered the phase II clinical trial, but the clinical development of the drug in Europe and Japan has been discontinued. The reason has not been reported. Fingolimod's structural analog, Amiselimod (MT-1303), is also in Phase II clinical research, but Biogen has suspended its clinical studies for CD based on the company's product line layout optimization. Ozanimod, a selective S1PR1 and S1PR5 agonist, was discovered by Receptos and is currently being advanced by Celgene for Phase II clinical trials for the treatment of UC and CD. In addition, Etrasimod (APD334, Arena Pharmaceuticals) is a selective agonist of S1PR1, S1PR4 and S1PR5 and is currently undergoing phase II clinical studies by Arena Pharmaceuticals for the treatment of UC.

  2.JAK inhibitor

In November 2012, the FDA approved the JAK inhibitor Tofacitinib (Xeljanz, Pfizer) for the treatment of active rheumatoid arthritis (RA) and adult patients who are ineffective or intolerant to methotrexate and other antirheumatic drugs. Tofacitinib, a potent inhibitor of JAK1 and JAK3, has a slightly weaker inhibitory effect on JAK2 and therefore blocks the production of various key cytokines (IL-2, IL-6, IFN-g and IL-17) that cause the onset of IBD. Tofacitinib was used in phase II clinical trials for patients with moderate to severe UC (OCTAVE trial). From 2012 to 2016, Pfizer also conducted a number of Phase III clinical trials for moderate to severe UC, and Tofacitinib showed significant efficacy relative to the placebo group. In contrast, the results of phase II clinical trials of Tofacitinib in patients with CD were not satisfactory, although some biochemical indicators improved in the high-dose group, but the overall treatment effect was not significantly different from the placebo group. Pfizer has discontinued Phase III clinical trials of Tofacitinib for CD therapy. In addition, Tofacitinib showed higher side effects than the placebo group in clinical trials, such as severe infections, which may be related to its low selectivity. For example, inhibition of JAK2 is thought to cause adverse reactions such as anemia, thrombocytopenia, and neutropenia. Therefore, the development of highly selective JAK inhibitors for the treatment of IBD will improve the safety of clinical use to some extent. Upadacitinib is a selective JAK1 inhibitor, which has a significant efficacy compared to placebo in a phase II clinical study of moderate to severe CD, and is safe in clinical safety associated with the drug's treatment of rheumatoid arthritis. similar.

Peficitinib is a selective JAK3 inhibitor and has completed a Phase II clinical trial of UC. However, Phase III clinical trials for UC have been discontinued. Interestingly, unlike other JAK inhibitors, clinical trials of Peficitinib have focused on patients with UC (rather than CD). Astellas is conducting a phase III clinical study of rheumatoid arthritis after discontinuing Phase III clinical trials of UC.

3.CCR9 antagonist

CCR9 is a chemokine receptor expressed on memory/effector CD4+ T cells and selectively binds to the chemokine CCL25. CCL25 is a cytokine mainly expressed in thymocytes and intestinal epithelial cells. When inflammation occurs in the intestine, its expression is significantly increased, and the interaction of lymphocytes into intestinal tissues is driven by interaction with its receptor CCR9. By inhibiting the interaction of CCR9 and CCL25, preventing the movement of lymphocytes into the intestinal tissue, thereby alleviating intestinal inflammation, can be used as a treatment for CD.

Vercirnon is an oral small molecule CCR9 selective antagonist developed by Glaxo Smith Kline for potential treatment of intestinal inflammatory diseases including CD and celiac disease. Vercirnon may accelerate the elimination of intestinal inflammatory T cells, so it is possible to promote clinical improvement by reducing the duration of IBD-related emergencies. Although Vercirnon showed good efficacy in the phase II clinical trial of moderate to severe CD, it did not have a significant effect in the phase III clinical trial compared to the placebo group, causing its subsequent development (including its clinical trial of UC) to be discontinued. . The reason for its failure is considered to be the problem of oral and subcutaneous injection pharmacokinetics caused by its poor physical and chemical properties, so that CCR9 cannot be continuously inhibited. Therefore, it is necessary to carry out rational drug design for its physical and chemical properties. And the prospects.

4. -4-4 integrin inhibitor

  Integrin on the surface of immune cells mediates its close adhesion to endothelial cells and mucosal epithelial cells. By inhibiting the activity of integrin, it is possible to inhibit the process of migration and accumulation of immune cells to the vicinity of the pathogen tissue, thereby improving inflammation. AJM300 is an orally active small molecule inhibitor of alpha-4 integrin, similar to the commercially available α4β7 integrin inhibitor Vedolizumab, which blocks lymphocytes (via adhesion molecules) from entering the inflammatory bowel. AJM300 is effective against colitis in IL-10 deficient T cell metastasis model mice. In phase II clinical trials, AJM300 has significant efficacy in the induction therapy of active UC patients. At present, AJM300 has completed Phase II clinical trials in active moderate UC adult patients who are not sensitive or intolerant to mesalazine or glucocorticoid in Japan. However, safety problems (ie progressive multifocal leukoencephalopathy) (PML)) may be a potential challenge.

5. Immunomodulator

Linomide (Roquinimex) is a quinoline derivative immunopotentiator that increases NK cell activity and cytotoxicity of macrophages. It also inhibits angiogenesis and reduces the production of TNF-[alpha]. Linomide has been used to treat certain cancers (including adjuvant treatment after bone marrow transplantation in acute leukemia) and autoimmune diseases such as multiple sclerosis and newly developed type 1 diabetes. However, due to its severe cardiovascular toxicity, many trials of the drug have been terminated. Laquinimod is a structural analog of Linomide and a potential orally available small molecule immunomodulator developed by Teva Pharmaceuticals for the treatment of various autoimmune diseases. The researchers found that laquinimod significantly improved colitis in IL-10-deficient mice, and that the reduction in inflammation was associated with the restoration of colon barrier function and the reduction of NF-kB signaling. A recent Phase II study demonstrated that laquinimod is effective and safe in patients with CD, and that it has also entered Phase III clinical trials for the treatment of moderate to severe CD.

Vidofludimus (a novel immunomodulator from 4SCAG) has a dual mechanism of action. On the one hand, Vidofludimus can reduce IL-17 production in the colon by inhibiting STAT3 and NF-kB activation; on the other hand, Vidofludimus can also act as DHODH (dihydrogen emulsion). An acid dehydrogenase inhibitor that inhibits the increase of T cells in the colon. Vidofludimus has significant efficacy in the DSS and TNBS mouse models as well as in the TNBS-induced rat enteritis model. Vidofludimus has shown good efficacy and safety in the IIa clinical trial of IBD, including CD and UC patients, with a response rate of 88.5% in patients with IBD.

6. Mucosal barrier enhancer

Developed by Lipid Therapeutics, LT-102 is a phospholipid agent that releases phosphatidylcholine. The mucous layer of the gastrointestinal tract is mainly composed of water, glycoproteins, lipids, other proteins and nucleic acids. Although phospholipids are a minor component of GI mucus, their hydrophobic surfaces established by virtue of amphiphilicity are indispensable for maintaining a complete barrier function. Surface phosphatidylcholine (PC) is the main mucin phospholipid. Compared with healthy people, UC patients have found that phosphatidylcholine (PC) in mucus of UC patients is significantly reduced and independent of inflammatory status. The lack of PC can lead to a decrease in surface hydrophobicity, leading to the intrusion of harmful substances in the lumen. However, PC is also involved in a variety of potential pro-inflammatory pathways, including tumor necrosis factor-alpha (TNF-alpha) signaling, activation of NF-kB cytokine expression, and mitogen-activated protein kinase. According to its inherent structure in the colonic mucosa, if PC reconstruction in colonic mucus of UC patients (via LT-102) can help restore mucus structure and density in UC patients, it can improve mucosal barrier function and prevent inflammation in UC patients. LT-102 is mainly used to improve the mucosal barrier function of patients with mild to moderate UC. It is currently in phase III clinical study.

  7. Summary and outlook

  As a chronic recurrent digestive system, IBD is not well defined and has no cure. Although the rise of antibody drugs has been very successful in the treatment of IBD, the development of small molecule IBD drugs has become a problem because of its poor patient compliance, high cost of treatment, and long-term use of drug resistance and adverse reactions. Problems that patients, doctors, pharmaceutical companies, and researchers pay close attention to can be expected to be developed in the near future for small molecule IBD drugs, and benefit IBD patients, in addition to the IBD candidate compounds in clinical studies described in this article. The follow-up will continue to summarize the potential compounds for small molecule treatment of IBD in preclinical studies.

 

 

2019 will be the key year for the development of new drugs for liver disease NASH

  Nonalcoholic steatohepatitis (NASH) is an extremely advanced form of nonalcoholic fatty liver disease, defined as the appearance of steatosis associated with inflammation and hepatocyte damage, leading to advanced liver fibrosis, cirrhosis, liver failure and The production of liver tumors. According to an article in Nature in 2017, NASH has become the second most common cause of liver transplantation in the United States following chronic hepatitis C and is expected to be the leading cause in 2020.

  The pharmaceutical market research institute ResearchAndMarkets has released a report that the NASH market is $729 million in 2016 and is expected to reach $20.576 billion by 2025. The compound annual growth rate (CAGR) for the 2017-2025 period will reach a staggering 46.1%.

  Despite the urgent medical needs, no drugs have been approved for NASH treatment so far. Fortunately, since Intercept announced the data on the drug Nacaliva treatment of NASH clinical projects in 2014, there have been many followers in this field.

  EvaluatePharma recently stated that 2019 will be a key year for NASH new drug development, with four teams in the field receiving critical clinical research data, including Intercept (see table below), which will also help each Large companies lay the future business position in the NASH field.

  NASH's new drug research and development field has not been smooth, and the recent NASH projects related to Gemphire and Shire have all caused problems. First, last Wednesday, the FDA did not allow Gemphire to initiate a long-term clinical study of gemcabene. The news was that the sub-chronic toxicology research data was mature, and the news caused the company's share price to plummet 51%. Recently, the company announced the cancellation of a clinical study of gemcabene, a pediatric fatty liver, due to an unexpected increase in liver fat, which caused the stock price to plunge by 60%. Shire has quietly abandoned the volixibat clinical project last month, but did not give any reason, the drug has been in Phase II clinical development.

  However, the above unfavorable news did not dampen the overall enthusiasm of investors in the NASH field, because there are two other potential NASH assets in the field of vision, namely Malmed aramchol and Madrigal MGL-3196.

Who will be the first to land in the market?

  At present, the industry believes that the first NASH drug will be born in Intercept's Ocaliva and Gilead's selonsertib. In 2019, the two parties will publish interim data on their Phase III clinical studies, and both parties hope to submit accelerated approvals to the US FDA.

  In the case of Intercept, analysts point out that Ocaliva needs to achieve at least one surrogate endpoint in the phase III clinical study REGENERATE: NASH remission and no fibrosis worsening or fibrosis relief and no NASH deterioration. In addition, Intercept must also prove the safety of Ocaliva, because the drug has been exposed to the risk of death and severe liver damage in the treatment of primary biliary cholangitis last September, so high doses of NASH will be closely watched. . In addition, Ocaliva failed in a Japanese NASH study and also attracted secondary attention from investors.

  It is worth noting that the biggest design differences in the key clinical studies listed above are the time points of NASH score and fibrosis change detection.

  This is very important, especially considering that Genfit's elafibranor failed to reach the primary endpoint of fibrosis and NASH remission at 12 months in phase II clinical trials. In addition, Aijian cenicriviroc was found in a phase II clinical study published in 2017. There was no significant difference in reducing fibrosis and no NASH deterioration. The drug is currently in phase III clinical trial, which is also the 12-month end point of the test. However, some investors suggested that Ai has the potential to modify the clinical design and focus on the patient population with a higher NASH baseline score.

  The industry is looking forward to the announcement of the above key clinical research data. And investment bank analyst Bernstein reminded that the key focus now is to establish strict clinical data.

Research: PD-1, CAR-T

  A team of Sloan recently published a study on the combination of CAR-T and PD-1 inhibitors in Natural Biotechnology. The authors invented a CAR-T that expresses mouse and human PD-L antibody fragments (single-chain variable region, scFv. mouse is RMP1-14, human E27), targeting two tumor antigens (CD19 for lymphoma) , MUC16 of ovarian cancer). The authors showed that this PD-1/CAR-T monotherapy was as effective or better than the CAR-T and PD-1 antibody combination in both homologous and heterologous mouse models. CAR-T can enrich and secrete PD-1 antibodies in tumor tissues because it expresses tumor antigens. The authors show that the secreted PD-1 antibody fragments not only protect these CAR-Ts, but also protect other T cells in tumor tissues, but basic Will not escape into the blood. However, CAR-T also has a longer life span and is more effective against TME immunosuppression because of PD-1 antibody protection.

  CAR-T and PD-1 inhibitors are the two most important technological advances in the new drug industry over the past 10 years, but despite their enormous power, they do have their own shortcomings. CAR-T currently only lists two blood tumor products. Although solid tumors have occasionally been successfully reported, such as the brain tumor CAR-T against IL13R in the previous year, there is no large-scale effective solid tumor CAR-T therapy. One major cause is the immunosuppressive environment of tumor TME, which also has cytokine-mediated immunosuppression such as PD-L1 in addition to immunosuppressive cells such as TAM and Treg. Although PD-1 antibody has a wide range of indications, most tumor response rates are around 20%. An important factor is the lack of tumor-specific T cells in tumor TME. CAR-T needs to fight immunosuppression in TME, and PD-1 needs to have enough tumor-specific T cells in TME. This technique solves the main problems faced by these two therapies with one stone and two birds.

  Depending on the angle of observation, this technique can be seen as a CAR-T with a PD-1 antibody as a bodyguard or a PD-1 antibody with a targeted delivery of a CAR-T transporter. The CAR-T expressing PD-1 antibody is more potent in in vitro and tumor cell co-culture experiments, and the secreted antibody fragment can bind to T cells that bypass PD-L1 expression. Compared with PD-1 antibody and CAR-T in vivo, this CAR-T expressing PD-1 antibody fragment showed greater survival advantage in different tumor models, even if the combination ratio of the two was at least equivalent. Some models show advantages. These CAR-T secreted PD-1 antibody fragments also protect bystander T cells in in vivo experiments. Although the secreted PD-1 antibody can move inside tumor tissues and bind to PD-1 on the surface of T cells other than CAR-T, the authors found that few antibody fragments entered the blood circulation by fluorescent label detection technology, so they were administered systemically. The PD-1 antibody is less toxic than the systemic system.

  Although the binding strength (nM level) of these antibody fragments was determined, but the drug concentration of the PD-1 antibody fragment secreted by the effective concentration of CAR-T in the tumor tissue was not published, PK/PD was somewhat questionable. However, mice injected with CAR-T also had a killing effect on another incompatible dark tumor (B16F10), indicating that the secreted PD-1 antibody fragment did reach therapeutic concentrations. In addition, no antibody fragment detected in the blood is related to the stability of the antibody fragment because its half-life has not been published. The article concludes that this technique can be used on other immunotherapies such as LAG-3, TIM-3, CTLA-4, which does not know whether it will affect future patent applications, no matter who develops these technologies. It used to happen because some people owe that a certain structural transformation can obviously improve the activity. As a result, some people took this sentence as evidence to say that the invention lacks creativity.

  The results of these studies, if replicated in the human body, will be an important advance. Targeted delivery of anticancer drugs, although a popular area of research, can indeed show very limited delivery systems that are enriched in tumor tissue. I have always thought that even if the drug is actually delivered to the tumor tissue, it will escape to the periphery, but today this study shows that this escape is at least not significant for the PD-1 antibody fragment. The entry of CAR-T into solid tumors is also a major problem with detoxification toxicity, but it is also a significant advancement if decompression inhibition can make some solid tumors suitable for CAR-T treatment. This design makes the two important technologies of PD-1 and CAR-T complement each other and warm up the group. Even if only part of it can be repeated in the clinic, it is a good technology.

Site Audit OZANIMOD （1306760-87-1 ）and Intermediate

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 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.

OZANIMOD 

Ozanimod RPC-1063 1306760-87-1, We have more than 6kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

OZANIMOD  Intermediates

1.Ozanimod Intermediates 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile 60899-34-5,

We have more than7kg in stock,  assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

2.Ozanimod Intermediates N-((S)-4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide 1306763-73-4, 

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

3.Ozanimod Intermediates (S)-1-amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride 1306763-57-4,

We have more than8kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

4.Ozanimod Intermediates (S)-tert-butyl (4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate 1306763-30-3,

We have more than7kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

5.Ozanimod Intermediates (S)-tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate 1306763-61-0, 

We have more than 6kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

6.Ozanimod Intermediates (S)-tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate 1306763-62-1, We have more than 7.5kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

7.Ozanimod Intermediates (S)-tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 1306763-63-2, We have more than 5.8kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

8.Ozanimod Intermediates (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate 1306763-64-3, We have more than 6.3kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

9.Ozanimod Intermediates (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 

1306763-71-2, We have more than 7.2kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

10.Ozanimod Intermediates (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 1306763-73-5, 

We have more than9.5kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

11.Ozanimod Intermediates (R)-N-((R)-4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide 1306763-28-9, 

We have more than 8.6kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Reference

1. Martinborough, Esther; Boehm, Marcus F.; Yeager, Adam Richard; Tamiya, Junko; Huang, Liming; Brahmachary, Enugurthi; Moorjani, Manisha; Timony, Gregg Alan; Brooks, Jennifer L.; Peach, Robert; et al. Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis of aryl(indanyl)​oxadiazoles and their use in the treatment of S1P1-​associated diseases. PCT Int. Appl. (2011), WO 2011060392 A1 20110519.