トファシチニブ 化學(xué)特性,用途語,生産方法
用途
トファシチニブ (Tofacitinib)は、ヤヌスキナーゼ阻害剤であり、免疫抑制剤?分子標(biāo)的薬のひとつ。
効能
抗リウマチ薬, ヤヌスキナーゼ(JAK)阻害薬
説明
In November 2012, the US FDA approved tofacitinib (also referred to as
CP-690550) for the treatment of adult patients with moderate to severely
active rheumatoid arthritis (RA) who have had an inadequate response or
intolerance to methotrexate. Tofacitinib is the first small molecule kinase inhibitor approved for the treatment of RA. Tofacitinib is an inhibitor of the four subtypes of Janus kinase (JAK): JAK1, JAK2, JAK3, and Tyk2. The JAKs are intracellular, nonreceptor tyrosine kinases that play important roles in the signal transduction pathway of many cytokines (e.g., interleukins 2, 4, 7, 9, 15, and 21) and are involved in the propagation of inflammation in RA. Tofacitinib acts by inhibiting the phosphorylation and activation of signal transducers and activators of transcription (STATs), thereby suppressing the production of inflammatory mediators in joint tissue. At the enzyme level, tofacitinib inhibits JAKs 1, 2, 3, and Tyk2 with IC
50s of 3.2, 4.1, 1.6, and 34 nM, respectively. At the cellular level, tofacitinib inhibits the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC
50s of 406, 56, and 1377 nM, respectively.
化學(xué)的特性
Light Pink to Pale Orange Solid
特性
Class: non-receptor tyrosine kinase
Treatment: RA, PA, JIA, UC
Oral bioavailability = 74%
Elimination half-life = 3.2 h
Protein binding = 40%
來歴
Tofacitinib (brand name: Xeljanz) is an oral JAK inhibitor developed by Pfizer Inc. It was first approved by the FDA on 6 November 2012 for the treatment of rheumatoid arthritis. Subsequently, Pfizer expanded its indications, securing approval for active psoriatic arthritis (December 2017), moderate to severe active ulcerative colitis (May 2018), and active polyarticular juvenile idiopathic arthritis (September 2020). Until December 2021, Xeljanz (tofacitinib) gained further FDA approval for treating active ankylosing spondylitis.
使用
CP-690550 is a pyrrolo[2,3-d]pyrimidine derivative, as Janus kinase inhibitor for treatment of rheumatoid arthritis
適応癥
The JAK family includes four isoforms, JAK1, JAK2, JAK3, and tyrosine kinase (TYK2). Ruxolitinib (Jakafi(R), Incyte Corp.) was the first approved JAK inhibitor, which inhibits both JAK1 and JAK2, used for the treatment of different types of myelofibrosis. Tofacitinib (Xeljanz(R), Pfizer) was approved by FDA as a JAK3-selective inhibitor for the treatment of rheumatoid arthritis and is one of the only two FDA-approved kinase inhibitors for non-oncological indications.
定義
ChEBI: A pyrrolopyrimidine that is pyrrolo[2,3-d]pyrimidine substituted at position 4 by an N-methyl,N-(1-cyanoacetyl-4-methylpiperidin-3-yl)amino moiety. Used as its citrate salt to treat moderately to severely
ctive rheumatoid arthritis.
臨床応用
Tofacitinib was approved for treating rheumatoid arthritis in 2012, joint pain and swelling, psoriatic arthritis in 2017, and ulcerative colitis in 2018. However, severe side effects observed during clinical studies prevented the FDA from approving more efficacious doses for the treatment of rheumatoid arthritis (RA). Tofacitinib also carries a black box warning for an increased risk of pulmonary embolism and death associated with the 10 mg BID dose.
トファシチニブ 上流と下流の製品情報(bào)
原材料
準(zhǔn)備製品