941678-49-5 Usage
Description
Ruxolitinib, also known as INCB018424 and Jakafi, is a potent and selective ATP-competitive inhibitor of Janus tyrosine kinases (JAK1 and JAK2) with IC50 values of 3.3 nM and 2.8 nM, respectively. It is a pyrazole derivative used in the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Ruxolitinib was approved by the U.S. FDA in November 2011.
Uses
Used in Pharmaceutical Industry:
Ruxolitinib is used as an antineoplastic agent for the treatment of myeloproliferative neoplasms (MPNs) such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It works by inhibiting the JAK-signal transducer and activator of transcription (STAT) pathway, which helps in reducing myeloproliferation, inducing apoptosis, and decreasing cytokine plasma levels.
Used in Dermatological Applications:
Ruxolitinib is used as a treatment for moderate to severe psoriasis, a chronic autoimmune skin disease. By inhibiting JAK1 and JAK2, it helps in reducing inflammation and alleviating the symptoms of psoriasis.
Used in Oncology Research:
Ruxolitinib is used as a research tool in the study of JAK-STAT signaling pathways and their role in various cancers. It helps in understanding the mechanisms of action and potential therapeutic applications in oncology.
Used in Drug Discovery and Development:
Ruxolitinib serves as a lead compound for the development of new drugs targeting JAK family kinases, which are involved in various inflammatory and immune disorders. Its structure and activity provide valuable insights for the design and synthesis of novel JAK inhibitors with improved selectivity and potency.
Pharmacological effects
Myelofibrosis (MF) is a rarely-occurring disease of myelodysplastic disorders. It is caused by the replacement of in vivo bone marrow by scar tissue, leading to the production of blood cells in the liver and spleen and other organs, which is characterized by splenomegaly, anemia, leukopenia, and thrombocytopenia, and different degrees of bone sclerosis. Symptoms include fatigue, abdominal discomfort, pain under the ribs, muscle and bone pain, itching and night sweats.
Ruxolitinib is the first oral medication approved by the US Food and Drug Administration (FDA) for the treatment of myelofibrosis. It is a small-molecule inhibitor of the tyrosine kinase (namely, JAK1 and JAK2) and is suitable for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia Vera myelofibrosis and post essential thrombocythemia myelofibrosis.
August 29, 2012, the EU has approved the first drug for the treatment of myelofibrosis, ruxolitinib. Ruxolitinib can be used for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia Vera myelofibrosis and post essential thrombocythemia myelofibrosis. Currently, ruxolitinib has been approved by more than 50 countries around the world, including the EU, Canada and some Asian, Latin American and South American countries.
US Novartis has obtained authorization from Incyte Company of the development and commercialization right of Ruxolitinib outside the United States. The European Commission and the FDA have both granted the status of Ruxolitinib as the orphan drug in the treatment of myelofibrosis. Currently, Incyte has sold it under the trade name Jakafi in the United States for the treatment of intermediate or high-risk myelofibrosis.
Figure 1 is the ruxolitinib tablet produced by the US Novartis Company (trade name: Jakafi)
Biological Activity
Ruxolitinib, INCB18424 is a potent and selective JAK1 and JAK2 inhibitor (IC50 were 2.7 and 4.5nM, respectively). It has potent anti-tumor and immunomodulatory activity. Ruxolitinib can inhibit IL-6 signal (IC50 = 281nM) and the proliferation of JAK2V617F + Ba/F3 cell. Ruxolitinib can also inhibit the STA3 phosphorylation of wild-type JAK2 and JAK2 V617F mutant inside the body of patients. Clinical application of it can significantly cause reduction in the circulating levels of inflammatory cytokines. Ruxolitinib also has an effective role in model of the adjuvant arthritis and the multiple-cause murine arthritis.
This information is edited by Xiongfeng Dai from lookchem.
Indications
Ruxolitinib is a kind of kinase inhibitor which is suitable for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia Vera myelofibrosis and post essential thrombocythemia myelofibrosis.
Dosage
1. For patients with platelet counts being greater than 200/μl, ruxolitinib should be applied at a start dose of 20 mg with being administered orally twice per day while for patients with platelet counts between 100/μl and 200/μl, they should apply a dose of 15mg twice a day.
2. Before starting to apply ruxolitinib treatment, you should perform complete blood count. Monitor the complete blood count in every 2-4 weeks and lower the adjusted dose for platelet count.
3. According to the result of the reaction, the patients can increase the dose to the maximum recommended dose of 25 mg twice per day. The patient should discontinue if the spleen gets no reduction or the symptoms are not improved, the patients should discontinue after 6 months.
Side effects
The most common hematological adverse reactions (incidence> 20%) is lower platelet counts and anemia. The most common non-hematologic adverse reactions (incidence> 10%) are bruising, dizziness and headache.
Other clinical research
Columbia University Medical Center has conducted a test of a drug designed to treat bone marrow diseases to investigate whether it can help people get rid of alopecia areata. The study found that, for human participating in human body test, including seven women and five men, after they have administrated a drug called Ruxolitinib, the symptoms of most people has been greatly alleviated. Part of their research has been published in the "Nature Medicine" magazine.
Originator
Incyte Corporation (United States)
Clinical Use
Tyrosine kinase inhibitor:
Treatment of disease related splenomegaly or
symptoms in patients with primary myelofibrosis
(MF), post polycythaemia vera (PV) myelofibrosis
or post-essential thrombocythemia myelofibrosis
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration increased by
clarithromycin and telithromycin, reduced dose of
ruxolitinib; concentration reduced by rifampicin.
Antifungals: reduce dose of ruxolitinib with
fluconazole, itraconazole, ketoconazole, posaconazole
and voriconazole.
Antipsychotics: avoid with clozapine, risk of
agranulocytosis.
Antivirals: reduce dose of ruxolitinib with
boceprevir, indinavir, lopinavir, ritonavir, saquinavir
and telaprevir.
Metabolism
Ruxolitinib is mainly metabolised by CYP3A4 (>50%),
with additional contribution from CYP2C9 to produce
2 major and active metabolites. About 74% of a dose is
excreted in the urine and about 22% via the faeces.
References
1) Verstovsek?et al. (2009),?Therapeutic potential of JAK2 inhibitors; Hematology Am. Soc. Hematol. Educ. Program,?2009(1)?636
2) Quintas-Cardama?et al. (2010),?Preclinical characterization of the selective JAK1/2 inhibitor INCB01824: Therapeutic implications for the treatment of myeloproliferative neoplasms; Blood,?115?3109
3) Farr et al. (2017) Targeting cellular senescence prevents age-related bone loss in mice; Nat. Med. 23 1072
4) Li?et al.?(2017)?Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia; Oncotarget?8?34687
Check Digit Verification of cas no
The CAS Registry Mumber 941678-49-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,4,1,6,7 and 8 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 941678-49:
(8*9)+(7*4)+(6*1)+(5*6)+(4*7)+(3*8)+(2*4)+(1*9)=205
205 % 10 = 5
So 941678-49-5 is a valid CAS Registry Number.
941678-49-5Relevant articles and documents
PROCESS AND INTERMEDIATES FOR PREPARING A JAK INHIBITOR
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, (2022/03/04)
The present invention is related to processes for preparing ruxolitinib, or a salt thereof, and related synthetic intermediates related thereto.
SYNTHESIS PROCESS OF RUXOLITINIB
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, (2019/02/05)
The present application falls within the field of drug synthesis, and in particular, the present application relates to a method for preparing ruxolitinib, and a method for preparing the intermediate and relevant intermediates used. The method comprises reacting a compound of formula II with a compound of formula IV or a salt thereof to obtain a compound of formula III, and then subjecting the compound of formula III to an acyl halogenation reaction, an amidation reaction, and a reaction dehydrating an amide to form a cyano group or removing the protecting group to prepare ruxolitinib. The method has the characteristics of brief steps, a high stereoselectivity, a high utilization ratio of atoms, mild reaction conditions and convenient post treatment. The method avoids using expensive asymmetric reaction catalysts, and is suitable for industrial production.
PROCESSES FOR THE PREPARATION OF RUXOLITINIB PHOSPHATE
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Page/Page column 29, (2016/03/19)
The present invention relates to processes for the preparation of ruxolitinib and ruxolitinib phosphate. The present invention also provides a compound of Formula IV, processes for its preparation, and its use for the preparation of ruxolitinib and ruxolitinib phosphate. The present invention provides ruxolitinib phosphate having a chiral purity of 99.96% and the compound of Formula IV having a chiral purity of 99.95%.