アプレミラスト 化学特性,用途語,生産方法
用途
アプレミラスト (Apremilast, 製品名 オテズラ, Otezla)は 尋常性乾癬 および乾癬性関節炎の治療薬。免疫系関連の炎症性疾患での有用性が期待されている。ホスホジエステラーゼ4 (PDE4）の選択的阻害作用と、関節リウマチの滑膜細胞からのTNF-αの生成を抑制する 。
効能
抗炎症薬, ホスホジエステラーゼ4阻害薬
商品名
オテズラ (セルジーン)
説明
Apremilast is the first and only oral phosphodiesterase IV (PDE-
4) inhibitor and anti-tumor necrosis factor alpha (TNFa) agent
launched in the USA by Celgene for the treatment of active psoriatic
arthritis (PsA). Apremilast was also approved for the treatment
of moderate to severe plaque psoriasis in the USA. Later,
this drug was also approved in the European Union (EU) for both
indications. Although multiple approaches to the synthesis of
apremilast have been described, the most likely process scale approach involves the construction of the challenging stereogenic
benzylic carbon center by catalytic asymmetric hydrogenation.
使用
Apremilast is an oral phosphodiesterase 4 inhibitor used in the treatment of adults with active psoriatic arthritis and adults with moderate to severe plaque psoriasis.
定義
ChEBI: Apremilast is a member of the class of isoindoles that is isoindole-1,3-dione substituted at position 4 by an acetamido group and at position 1 by a 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl group. Used for treatment of psoriatic arthritis. It has a role as a phosphodiesterase IV inhibitor and a non-steroidal anti-inflammatory drug. It is an aromatic ether, a N-acetylarylamine, a sulfone and a member of phthalimides.
過量投与
Apremilast was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mg twice daily) for 4.5 days without evidence of dose limiting toxicities. In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment is instituted. In the event of overdose, symptomatic and supportive care is advised.
酵素阻害剤
This thalidomide-like psoriasis drug (FW = 460.50 g/mol; CAS 608141-41-9; Solubility: 90 mg/mL DMSO; <1 mg/mL H2O), also known as CC-10004, Otezla? and N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methyl-sulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, is a potent, orally active phosphodiesterase inhibitor that targets phosphodiesterase PDE4 (IC50 = 74 nM), itself a proinflammatory mediator, and TNF-α, IC50 = 77 nM. Apremilast inhibits PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-γ and tumor necrosis factor-α (TNF-α), and interleukins IL-2, IL-12 and IL- 23 from human rheumatoid synovial membrane cultures. Apremilast significantly reduces clinical scores in both murine models of arthritis over a ten-day treatment period and maintains healthy joint architecture in a dose-dependent manner. Unlike rolipram, however, apremilast demonstrated no adverse behavioral effects in na?ve mice. Otezla is specifically indicated by the Food & Drug Administration for the treatment of patients with moderate to severe plaque psoriasis who are typically candidates for phototherapy or systemic therapy. That said, the specific mechanism(s) for therapeutic action in psoriatic arthritis patients and psoriasis patients is unclear.
Mode of action
Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. These pro- and anti-inflammatory mediators have been implicated in psoriatic arthritis and psoriasis.
アプレミラスト 上流と下流の製品情報
原材料
準備製品