タミバロテン 化学特性,用途語,生産方法
外観
白色, 結晶～粉末
溶解性
エタノール(95)にやや溶けやすく、アセトニトリルに溶けにくく、水にほとんど溶けない。
用途
レチノイドレセプターを介するさまざまな細胞内伝達ツール。
効能
抗悪性腫瘍薬, レチノイン酸受容体(RAR)作動薬
商品名
アムノレイク (東光薬品工業)
説明
Tamibarotene, a selective agonist of the retinoic acid receptor, was launched in
Japan as an oral treatment for relapsed or refractory acute promyelocytic
leukemia (APL). APL is a form of acute myeloid leukemia (AML) characterized by
a deficiency in mature blood cells and an excess of immature cells called promyelocytes
in the bone marrow and peripheral blood. The current standard of care
for APL includes treatment with all-trans-retinoic acid (ATRA), either alone or in
combination with chemotherapy. ATRA is a high affinity ligand for two types of
nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR),
each of which has three subtypes (-α, -β, and -γ). Activation of RARα by ATRA
causes promyelocytes to differentiate and mature, thereby inhibiting their proliferation
and inducing disease remission. Although ATRA is one of the most clinically
successful retinoids, its usage is hampered by the high rate of adverse effects,
instability, and the appearance of ATRA-resistant leukemia cells.Adverse events included retinoic acid syndrome, hyperleukocytosis, xerosis,
cheilitis, hypertriglyceridemia, and hypercholesterolemia; however, these side effects
were generally milder than with ATRA, which all patients had received previously.
Examination of human samples taken from Phase II and III clinical trials revealed
that fecal excretion was the major elimination route, and the metabolism of tamibarotene
occurred primarily through hydroxylation and taurine conjugation. In
vitro, the plasma protein binding of tamibarotene is shown to be ＞98% in rats,
dogs, and humans. Tamibarotene is synthesized from 5,5,8,8-tetramethyl-5,6,7,
8-tetrahydronaphthalene in a four-step sequence consisting of regioselective nitration
in the 2-position, reduction of the nitro group by hydrogenation to produce
the corresponding aniline derivative, acylation of the aniline intermediate with
4-(carbomethoxy)benzoyl chloride, and hydrolysis of the methyl ester.
化学的特性
Crystalline Solid
使用
Tamibarotene, a retinoic acid receptor-α(RARα) agonist,
was approved for the treatment of relapsed or refractory
acute promyelocytic leukemia (APL) in Japan on June, 2005
and is currently marketed by Nippon Shinyaku Co. This
novel drug has shown high remission rate among patients
who have recurrent disease after all trans retinoic acid therapy.
定義
ChEBI: A dicarboxylic acid monoamide resulting from the condensation of one of the carboxy groups of terephthalic acid with the amino group of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-amine.
生物活性
Retinoic acid receptor α (RAR α ) agonist that induces differentiation (ED 50 = 0.79 nM) and apoptosis of HL-60 cells in vitro . Exhibits antiproliferative effects against a variety of human tumor cells lines (mean values of 35, 40 and 60% growth inhibition at 0.1, 1 and 10 μ M respectively) and displays anticancer activity against acute promyelocytic leukemia in vivo .
タミバロテン 上流と下流の製品情報
原材料
準備製品