レトロゾール 化學(xué)特性,用途語,生産方法
用途
レトロゾール（英: letrozole）は乳癌の治療で用いられるアロマターゼ阻害薬の一種であり、アロマターゼから作られるエストロゲンの産生を抑えることによってホルモン依存性の腫瘍を抑える効果が期待される。
効能
抗悪性腫瘍薬, エストロゲン生合成阻害薬
商品名
フェマーラ (ノバルティスファーマ)
説明
Letrozole, also known as Femara, is an orally active aromatase inhibitor that works by competitively inhibiting aromatase. This inhibition prevents the conversion of androgens to estrogen (estrogen stimulates breast tissues and breast cancer reoccurrence) and gonadal steroidogenesis. It can be used for the treatment of breast cancer that is hormonally-responsive or has an unknown receptor status in postmenopausal women. Besides this, Letrozole also has some off-label use such as ovarian stimulation, pretreatment of termination of pregnancy, treatment of gynecomastia, treatment of endometriosis, and promoting spermatogenesis for male patients of nonobstructive azoospermia.
化學(xué)的特性
white to light yellow crystal
來歴
Letrozole was discovered by scientists at the Swiss company Ciba-Geigy AG (now Novartis AG) In the 1980s while screening compounds for their ability to inhibit aromatase. Letrozole was far more potent than any other aromatase inhibitor discovered. As a result, its development was accelerated, leading to its approval in 1996 for the treatment of advanced breast cancer in France and other European countries. The following year letrozole was approved by the U.S. Food and Drug Administration. In addition to the drug’s general approval for the treatment of advanced breast cancer, in later years it was approved for multiple and specific applications. For example, in 2001 letrozole was approved in the United Kingdom specifically for the first-line treatment of advanced breast cancer, and in 2004 it was approved in the United States for what is known as extended adjuvant therapy.
使用
Letrozole has been used:
- in organoid growth assay to determine its inhibitory capacity(48)
- to investigate steroid receptor coactivator-1 (SRC-1) mediated endogenous estrogen regulation of hippocampal PSD-95(49)
- to determine its effects on tumor-induced hyperalgesia(50)
- for hormonal manipulation in rats(51)
- to study its effects on lipocalin-2 (Lcn2)(52)
- to determine its effects on mechanical hyperalgesia and aromatase expression(53)
一般的な説明
Letrozole, 4,4'-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile (Femara), is used for most of thesame indications as anastrozole. It reduces concentrations ofestrogens by 75% to 95%, with maximal suppressionachieved within 2 to 3 days. Letrozole is specific for aromataseinhibition, with no additional effects on adrenal corticoidbiosynthesis. CYPs 3A4 and 2A6 are involved in themetabolism of letrozole to the major carbinol metabolite,which is inactive. The loss of the triazole ring, which is involvedin coordination of the heme iron, would explain theloss of activity. Letrozole strongly inhibits CYP2A6 invitro, with moderate inhibition of CYP2C19. The effect ofthis in vitro inhibition on the pharmacokinetics of coadministereddrugs is unknown. Tamoxifen reduces the levels ofletrozole significantly if they are used together, so combinationtreatment with these agents is not recommended.
生物活性
Letrozole is a potent, cell-permeable inhibitor of aromatase (IC50 = 2 nM). It inhibits proliferation of estrogen receptor-positive (ER+) MCF-7 cells when used alone at concentrations ranging from 0.1 to 100 nM and when used at a concentration of 10 nM in combination with testosterone or 4-androstene-3,17-dione. It also reduces matrix metalloproteinase-2 (MMP-2) and MMP-9 levels in MCF-7 cells when used at a concentration of 10 nM. Letrozole (10 μg per day) reduces tumor growth in an MCF-7Ca ovariectomized-mouse xenograft model. Formulations containing letrozole have been used in the treatment of postmenopausal breast cancer.
作用機序
Inhibition of arom atase by letrazole is competitive and highly specific , with no effect on enzymes that are responsible for the production of glucocorticosteroids and mineralocorticosteroids. This agent is significantly more effective than tamoxifen in treating horm one-dependent cancer.
臨床応用
Femara was launched in France and the UK for second-line treatment of
advanced breast cancer. Letrazole can be synthesized in two steps from 4-
bromomethyl-benzonitrile with 1,2,4-triazole and is a third generation aromatase
inhibitor. It is a highly specific inhibitor of P450
arom which prevents the conversion of
androstenedione to estrone. The reduction of plasma estrogen was immediate and
long lasting. This is accomplished with no inhibition of other steroid biosynthesis
making it the most selective aromatase inhibitor tested. Letrazole has remarkable
antitumor activity, is well tolerated and has no toxic side effects. It is 10,000 times
more potent than aminoglutethimide, in vivo, the first well established aromatase
inhibitor.
參考文獻
https://www.drugbank.ca/drugs/DB01006
https://en.wikipedia.org/wiki/Letrozole
レトロゾール 上流と下流の製品情報
原材料
準(zhǔn)備製品