2-(ジフルオロメチル)-L-オルニチン 化学特性,用途語,生産方法
効能
抗悪性腫瘍薬, 抗原虫薬, オルニチン脱炭酸酵素阻害薬
説明
Metcalf et al.reported the synthesis of eflornithine (difluoromethyl ornithine [DFMO]) in 1978.
Their interest arose from the desire to prepare ornithine decarboxylase (ODC) inhibitors as tools
for studying the role of polyamines as regulators of growth processes. Ornithine decarboxylase
catalyzes the conversion of ornithine to putrescine (1,4-diaminobutane), which in turn leads to the
formation of the polyamines, spermine, and spermidine. It was not until 1980 that Bacchi et al.
demonstrated the potential of DFMO in the treatment of trypanosomiasis.
使用
Labelled Eflornithine. Irreversible inhibitor of ornithine decarboxylase, an enzyme involved in polyamine biosynthesis. Antineoplastic; antipneumocystic; antiprotozoal (Trypanosoma). Used in the treatment of hirsutism.
適応症
Eflornithine (difluoromethyl ornithine, Ornidyl) is a
unique antiprotozoal agent in that its mode of action involves
inhibition of a specific enzyme, ornithine decarboxylase.
In eukaryotes, decarboxylation of ornithine is
required for biosynthesis of polyamines, which are important
in cell division and differentiation.
Eflornithine is given intravenously, and about 80%
of the drug is excreted in the urine within 24 hours. It
does not bind significantly to plasma proteins and has a
terminal plasma half-life of about 3 hours. It crosses the
blood-brain barrier and is one of the drugs of choice for
treating the hemolymphatic and meningoencephalitic
stage of T. brucei-gambiense. The most significant side
effects are anemia and leukopenia. Oral therapy is associated
with considerable gastrointestinal toxicity.
Diarrhea, thrombocytopenia, and seizures are occasionally
reported.
作用機序
Difluoromethyl ornithine is a suicide inhibitor of ODC, a pyridoxal phosphate–dependent enzyme. Evidence suggests that cysteine-360 in ODC is the site of eflornithine
alkylation. Alkylation of ODC blocks the synthesis of putrescine, the rate-determining step in
the synthesis of polyamines. Mammalian ODC also may be inhibited, but because the turnover of
ODC is so rapid in mammals, eflornithine does not produce serious side effects.
臨床応用
Eflornithine is used for the treatment of West African sleepingsickness, caused by Trypanosoma brucei gambiense.It is specifically indicated for the meningoencephaliticstage of the disease. Eflornithine is a myelosuppressivedrug that causes high incidences of anemia, leukopenia,and thrombocytopenia. Complete blood cell counts must bemonitored during the course of therapy.The irreversible inactivation of ornithine decarboxylaseby eflornithine is accompanied by decarboxylation andrelease of fluoride ion from the inhibitor, suggesting enzyme-catalyzed activation of the inhibitor. Only the (—) isomer,stereochemically related to L-ornithine, is active.
Eflornithine is supplied as the hydrochloride salt. It may beadministered either intravenously or orally. Approximately80% of the unchanged drug is excreted in the urine.Penetration of eflornithine into the CSF is facilitated by inflammationof the meninges.
副作用
Side effects
reported for eflornithine consist of anemia, diarrhea, and leukopenia.
2-(ジフルオロメチル)-L-オルニチン 上流と下流の製品情報
原材料
準備製品