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Filgotinib, the molecular formula is C21H23N6O3S, CAS 1206161-97-8, and the molecular weight is 441.52 g/mol. It is white solid powder, odorless. Soluble in DMSO at room temperature, slightly soluble in ethanol, insoluble in water. It has good thermal stability and can be stored for a long time under stable conditions. It is a neutral ligand and cannot directly participate in redox reactions. However, when complexed with other metal ions, redox properties can be exhibited. In clinical trials, it has been proven to be relatively safe at therapeutic doses, but in animal experiments, high-dose products may cause liver toxicity and reproductive toxicity. It is a small molecule compound for the oral treatment of rheumatoid arthritis and other autoimmune diseases. However, the primary chemicals produced by Shaanxi Achieve chem-tech Co.,Ltd are only used in laboratories.
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Chemical Formula |
C21H23N5O3S |
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Exact Mass |
425 |
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Molecular Weight |
426 |
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m/z |
425 (100.0%), 426 (22.7%), 427 (4.5%), 427 (2.5%), 426 (1.8%), 428 (1.0%) |
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Elemental Analysis |
C, 59.28; H, 5.45; N, 16.46; O, 11.28; S, 7.53 |
The molecular structure of it is as follows:
Wherein, the central ring is composed of a carbazole derivative and a pyrrolopyrimidine derivative, and the two are connected through a methyl group. There is a pyridoxone oxygen atom, an alkylamino group and an acrylamide group on the heterocycle. The whole molecule presents a twisted helical shape, which enables product to have high selectivity and affinity for the JAK1 signaling pathway.
It is a chemically stable small molecular compound that is not prone to decomposition reactions under normal conditions. However, since it is an electrophilic compound, addition reactions or nucleophilic substitution reactions may occur in water.
In addition, it may also participate in the amide hydrolysis reaction, which hydrolyzes the acrylamide group into acrolein and amino compounds. This hydrolysis reaction can occur in vivo or in vitro metabolism, and may affect the pharmacological activity and metabolic kinetics of product.
In general, as an oral drug, it needs to be absorbed in the digestive tract and enter the blood circulation to exert pharmacological effects. Therefore, its reaction properties have a certain impact on drug absorption, metabolism and pharmacodynamics, which need to be considered in the process of drug design and preparation.
Filgotinib is an oral small molecule compound for the treatment of rheumatoid arthritis and other autoimmune diseases. It is a Janus kinase (JAK) inhibitor that blocks multiple signaling pathways in cells, reducing inflammation and overactive immune system. All uses of product in the clinical and pre-clinical fields will be described in detail.
1. Treatment of rheumatoid arthritis:
Rheumatoid arthritis is a common autoimmune disease in which patients often experience symptoms such as joint swelling and pain. It is a selective JAK1 inhibitor that can alleviate the symptoms of rheumatoid arthritis by modulating the immune system's response. A number of clinical trials have proven that it can significantly improve symptoms such as joint function, pain and swelling in patients with rheumatoid arthritis.
2. Treatment of inflammatory bowel disease:
Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, is a chronic, irreversible intestinal inflammation. It can reduce the intestinal inflammatory response by inhibiting the JAK1 signaling pathway, and is expected to become a new drug for the treatment of inflammatory bowel disease. Preliminary clinical trial results show that it has good efficacy in the treatment of inflammatory bowel disease.
3. Treat psoriasis:
Psoriasis is a common autoimmune skin disease characterized by plaques, erythema, and scaling of the skin. It can help regulate the activity of the immune system and reduce the symptoms of psoriasis patients by inhibiting the JAK1 signaling pathway. An ongoing Phase II clinical trial is evaluating the safety and efficacy of product in the treatment of psoriasis.
4. Treatment of systemic lupus erythematosus:
Systemic lupus erythematosus is an autoimmune disease of unknown etiology that causes symptoms such as muscle pain, fatigue and fever. It can reduce the inflammatory response and the activity of the immune system in patients with systemic lupus erythematosus by inhibiting the JAK1 signaling pathway, thereby reducing the symptoms of patients. Currently, it is undergoing a clinical trial to evaluate its safety and efficacy in the treatment of systemic lupus erythematosus.
5. Treatment of dry eye disease:
Dry eye disease is a common eye disease. Patients will feel dry eyes, stinging, eye fatigue and other symptoms. It may reduce symptoms in patients with dry eye disease by suppressing the inflammatory response in the immune system. An ongoing preclinical study shows that it has good potential for the treatment of dry eye disease.
Overall, Filgotinib is a broad-spectrum therapeutic drug that can relieve symptoms associated with various autoimmune diseases by modulating the activity of the immune system. In the future, with the release of more clinical trial results, it is expected to become a new drug for the treatment of various autoimmune diseases.
6. Core indications and mechanism of action
1. Rheumatoid arthritis (RA)
Mechanism of action: Fego tinib, as a selective JAK1 inhibitor, targets the signal transduction of pro-inflammatory cytokines such as IL-6 and TNF - α. By inhibiting the JAK1-STAT3 pathway, reducing the levels of inflammatory factors in synovitis, and slowing down the process of joint destruction.
Clinical trials:
The DARWIN series of studies: Phase III clinical trials (DARWIN 1/2/3) showed that at a dose of 200mg QD, the ACR20 response rate (20% improvement in joint symptoms) reached 76% -80%, significantly better than the placebo group (43% -50%).
Long term efficacy: The Open Label Extended Study (GLADIUS) showed that continuous treatment for 4 years reduced the risk of joint imaging progression (such as bone erosion) by 46% and achieved a sustained remission rate of 60%.
Clinical advantages: Compared with traditional synthetic DMARDs such as methotrexate, fegolotinib has a faster onset of action (improving pain within 2 weeks) and is still effective in refractory RA patients (those with poor response to biologics).
2. Ulcerative colitis (UC)
Therapeutic status: The first approved oral JAK inhibitor for moderate to severe UC, filling the treatment gap for patients with insufficient response to biologics such as TNF monoclonal antibodies.
Key experiment:
SELECTION Study: A total of 2040 patients were enrolled, and the clinical remission rate (Mayo score ≤ 2) in the 200mg QD group after 10 weeks of induction therapy was 26.1%, while the remission rate after 58 weeks of maintenance therapy was 37.2%.
Dose optimization: For individuals weighing less than 50kg or with moderate liver and kidney function impairment, the dosage should be reduced to 100mg QD to balance efficacy and safety.
Function characteristics: By inhibiting the JAK1-STAT1/3 pathway, reducing cytokines such as IFN - γ and IL-17, improving intestinal mucosal healing, and reducing bleeding and diarrhea.
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3. Psoriatic arthritis (PsA)
Clinical evidence:
MANTA RAy study: Treatment with 200mg QD for 13 weeks resulted in a response rate of 48% for skin symptoms (PASI score decrease ≥ 50%) and 56% for joint symptoms (ACR20).
Mechanism of action: Inhibit the JAK1-STAT1/3 pathway, reduce cytokines such as IL-17 and IL-23, and improve plaque lesions and attachment inflammation.
Clinical advantages: For PsA patients with insufficient response to methotrexate, the combination of non gefitinib and local treatment can significantly improve their quality of life.
Filgotinib is an oral small molecule compound for the treatment of rheumatoid arthritis and other autoimmune diseases. All synthetic methods for product will be described.
The synthesis of it begins with the amination of 5-fluoro-2-methylaniline. First, react 5-fluoro-2-methylaniline with sodium isopropyl bisulfate to generate the corresponding amide intermediate. Then, under the action of sodium carbonate and methanol, the amide intermediate was decomposed to give 5-fluoro-2-methylaniline.
Next, put 5-fluoro-2-methylaniline and cis- and trans-acrylonitrile together with N,N-dimethylformamide (DMF) and triethylamine into the reaction flask respectively, and use DCC (di Carboxyl chloride chemistry) or DIC (N,N'-dicyclohexylcarbamic anhydride) as activators. After the reaction, trans and cis-2-[(5-fluoro-2-methylphenyl)amino]-3-pyrrolidine-1-carbonitrile were obtained as two chiral isomers. This step reaction is also called Ugi reaction.
In the next step, the methylated tetracycline in the trans isomer is selectively oxidized using a selective catalyst in the presence of formic acid and ethylene glycol to form the -CHO substituent. After careful optimization, a high yield product was obtained.
Then, the trans isomer-2-[(5-fluoro-2-methylphenyl)amino]-3-(4-methoxymethylphenylthio)-pyrrolidin-1-ol was mixed with N- Chlorobutyldimethylcarbamate (CBDA) for bridging cyclization. The reaction conditions were carried out at a low temperature of -78°C under a nitrogen atmosphere. The final product is it.
Above is the detailed description of all synthetic methods of product. These methods are developed and optimized in sophisticated, time-consuming laboratory operations to increase yield and product purity and ensure product quality meets pharmaceutical industry standards.
Future Directions and Challenges
● Personalized Medicine
As our understanding of the pathophysiology of autoimmune diseases continues to evolve, there is a growing interest in personalized medicine approaches that tailor treatment to individual patient characteristics. Filgotinib's high selectivity for JAK1 makes it an attractive candidate for personalized therapy, as it may offer improved efficacy and safety in specific patient populations. Future research will focus on identifying biomarkers that can predict response to filgotinib and guide treatment decisions.
● Combination Therapies
Combination therapy with filgotinib and other DMARDs or biologics may enhance therapeutic efficacy and reduce the risk of adverse events. Ongoing clinical trials are exploring the potential benefits of combining filgotinib with agents such as tumor necrosis factor (TNF) inhibitors, IL-17 inhibitors, and B-cell depleting agents. These studies will provide valuable insights into the optimal use of filgotinib in combination therapy regimens.
● Regulatory and Market Challenges
Despite its promising clinical profile, filgotinib has faced regulatory challenges, particularly in the United States, where the Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) in 2020, citing concerns about the overall benefit-risk profile of the drug. This decision has delayed the approval of filgotinib in the US market, although it remains available in Europe and Japan. Addressing these regulatory concerns and conducting additional studies to further characterize the safety and efficacy of filgotinib will be crucial for its global approval and commercial success.
Frequently Asked Questions
Why is its active metabolite 10 times less effective than the original drug, but still the main contributor to the in vivo efficacy?
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Because the systemic exposure of this metabolite in the human body is 16-20 times higher than that of the original drug, it is sufficient to compensate for its insufficient efficacy. The combined effect of the two prolonged the inhibition time of the drug on the JAK1 pathway.
What are the unique advantages of drug interaction risk compared to other JAK inhibitors?
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It is not metabolized by liver CYP450 enzyme and is a substrate for P-glycoprotein. Therefore, when used in combination with common antifungal drugs, antibiotics, or cardiovascular drugs, the likelihood of significant interactions is low and usually does not require dose adjustment.
Why has rheumatoid arthritis not yet been approved for treatment in the United States?
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The US drug regulatory authorities are concerned about potential testicular toxicity. The request for more clinical research data on its impact on sperm parameters in 2020 directly led to a delay in the evaluation of its indications for RA in the United States.
Is there a significant difference in efficacy and safety between 200mg and 100mg doses in the treatment of rheumatoid arthritis?
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In terms of efficacy, studies have shown that there is not much difference between the two. But the latest long-term safety analysis reveals that there may be a potential dose correlation between a 200mg dose and higher risk of shingles, malignancy, and all-cause mortality in patients over 65 years old.
What specific impact will the efficacy of previous treatment for patients with complex ulcerative colitis be affected?
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Research has found that the more advanced therapies (such as biologics) that have been used in the past, the poorer the efficacy of non gefitinib may be. This indicates that its sequential position in the treatment pathway may affect its actual effectiveness.
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