米非司酮
描述
米非司酮，也称为其开发代号 RU-486，是一种合成类固醇化合物，化学式为 C29H35NO2 。它主要以其在药物流产和早期流产管理中的应用而闻名。 米非司酮通过阻断孕激素的作用机制起效，孕激素对维持妊娠至关重要 .
作用机制
米非司酮既是孕激素受体又是糖皮质激素受体的拮抗剂。通过与孕激素受体结合，它阻止了激素发挥作用，导致子宫内膜的分解和妊娠的终止。 在较高剂量下，米非司酮还会阻断糖皮质激素受体，这在治疗库欣综合征等疾病方面有用 .
科学研究应用
米非司酮具有广泛的科学研究应用，包括：
化学： 用作研究类固醇合成和反应的模型化合物。
生物学： 研究其对激素受体和细胞途径的影响。
医学： 主要用于药物流产、治疗库欣综合征和管理子宫内膜异位症.
工业： 用于开发新的药物制剂和药物递送系统.
生化分析
Biochemical Properties
Mifepristone acts as a competitive progesterone receptor antagonist . In the absence of progesterone, mifepristone acts as a partial agonist . It works by blocking the effects of progesterone, making both the cervix and uterine vessels dilate and causing uterine contraction . Mifepristone is also a glucocorticoid receptor antagonist .
Cellular Effects
Mifepristone has been shown to inhibit ovarian cancer cell proliferation in a dose- and time-dependent manner . It also induced fewer alveoli, enlarged alveolar lumina, and altered the levels of hormones such as estrogen, progesterone, prolactin, growth hormone, corticosterone, and oxytocin, as well as the mRNA expression of these hormonal receptors during pregnancy or early lactation .
Molecular Mechanism
Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses . It works by blocking the effects of progesterone, which is necessary for a pregnancy to continue . Mifepristone’s inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua .
Temporal Effects in Laboratory Settings
In a 24-week multicenter, open-label trial, mifepristone produced significant clinical and metabolic improvement in patients with Cushing’s syndrome with an acceptable risk-benefit profile during 6 months of treatment . Mifepristone treatment reduced cellular proliferation and viability of all UM cell lines studied in a concentration-dependent manner .
Dosage Effects in Animal Models
In animal models, mifepristone administration at the dose of 1.20 mg/kg body weight on pregnancy day 4 caused a significant reduction in milk production on lactation day 1, lactation day 2, and lactation day 3 . Mifepristone also induced an increase in the weight of epididymal, perirenal, and gluteofemoral adipose tissues .
Metabolic Pathways
Mifepristone is extensively metabolised by demethylation and hydroxylation, the initial metabolic steps are catalysed by the cytochrome P450 (CYP) enzyme CYP3A4 . The three most proximal metabolites, namely the monodemethylated, didemethylated, and hydroxylated metabolites of mifepristone, all retain considerable affinity toward the human progesterone and glucocorticoid receptors .
Transport and Distribution
The serum transport protein α1-acid glycoprotein (AAG) regulates the serum kinetics of mifepristone . Binding to AAG limits the tissue availability of mifepristone, explaining the low metabolic clearance rate of 0.55 L/kg/day and the low volume of distribution of mifepristone .
Subcellular Localization
Mifepristone markedly reduces cdk2 activity likely due to increased association of cdk2 with the cdk inhibitors p21 cip1 and p27 kip1 and reduced nuclear cdk2/cyclin E complex availability . This suggests that mifepristone may regulate mitochondrial function through the control of mitochondrial gene expression .
准备方法
合成路线和反应条件： 米非司酮的合成通过一个多步骤过程进行，涉及多个关键中间体。合成从 11β-[4-(二甲氨基)苯基]-17β-羟基-17α-(1-丙炔基)雌甾-4,9-二烯-3-酮的制备开始。 然后将这种中间体进行各种化学反应，包括羟基化和烷基化，以生成最终化合物 .
工业生产方法： 在工业环境中，米非司酮采用湿法制粒法生产。这包括将活性药物成分与赋形剂（如淀粉和微晶纤维素）混合，然后用水/醇混合物制粒。 然后将颗粒干燥并压成片剂 .
化学反应分析
反应类型： 米非司酮会发生多种化学反应，包括：
氧化： 米非司酮可以被氧化形成各种代谢产物。
还原： 还原反应可以修饰米非司酮中的酮基。
取代： 取代反应可以在二甲氨基上发生.
常见试剂和条件：
氧化： 常见的氧化剂包括高锰酸钾和三氧化铬。
还原： 采用硼氢化钠和氢化铝锂等还原剂。
取代： 卤代烷和胺等试剂用于取代反应.
主要生成产物： 这些反应生成的主要产物包括各种羟基化和脱甲基化代谢物，例如 N-脱甲基米非司酮和 22-羟基米非司酮 .
相似化合物的比较
米非司酮属于一类称为孕激素受体拮抗剂的化合物。类似的化合物包括：
左炔诺孕酮： 用于紧急避孕，但主要起效机制是作为孕激素而不是拮抗剂.
醋酸乌利司他： 另一种孕激素受体调节剂，用于紧急避孕和治疗子宫肌瘤.
米非司酮的独特性： 米非司酮作为孕激素和糖皮质激素受体拮抗剂的独特能力使其在同类化合物中脱颖而出。 这种双重作用使其在从终止妊娠到管理激素紊乱的各种医学应用中非常有效 .
属性
IUPAC Name |
(8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C29H35NO2/c1-5-15-29(32)16-14-26-24-12-8-20-17-22(31)11-13-23(20)27(24)25(18-28(26,29)2)19-6-9-21(10-7-19)30(3)4/h6-7,9-10,17,24-26,32H,8,11-14,16,18H2,1-4H3/t24-,25+,26-,28-,29-/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
VKHAHZOOUSRJNA-GCNJZUOMSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC#CC1(CCC2C1(CC(C3=C4CCC(=O)C=C4CCC23)C5=CC=C(C=C5)N(C)C)C)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CC#C[C@@]1(CC[C@@H]2[C@@]1(C[C@@H](C3=C4CCC(=O)C=C4CC[C@@H]23)C5=CC=C(C=C5)N(C)C)C)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C29H35NO2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID5023322 |
Source
|
| Record name | Mifepristone | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID5023322 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
429.6 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Mifepristone | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014972 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
7 [ug/mL] (The mean of the results at pH 7.4), Poorly soluble, Very soluble in methanol, chloroform, and acetone and poorly soluble in water, hexane, and isopropyl ether., In water, 5.0X10-2 mg/L at 25 °C /Estimated/, 3.36e-03 g/L |
Source
|
| Record name | SID11533034 | |
| Source | Burnham Center for Chemical Genomics | |
| URL | https://pubchem.ncbi.nlm.nih.gov/bioassay/1996#section=Data-Table | |
| Description | Aqueous solubility in buffer at pH 7.4 | |
| Record name | Mifepristone | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00834 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | MIFEPRISTONE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6841 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Mifepristone | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014972 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Vapor Pressure |
8.0X10-14 mm Hg at 25 °C /Estimated/ |
Source
|
| Record name | MIFEPRISTONE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6841 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Mechanism of Action |
The anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites. Based on studies with various oral doses in several animal species (mouse, rat, rabbit and monkey), the compound inhibits the activity of endogenous or exogenous progesterone. The termination of pregnancy results. In the treatment of Cushing's syndrome, Mifepristone blocks the binding of cortisol to its receptor. It does not decrease cortisol production but reduces the effects of excess cortisol, such as high blood sugar levels., Mifepristone competitively inhibits the actions of progesterone at progesterone-receptor sites, resulting in termination of pregnancy.The combination of mifepristone and misoprostol causes expulsion of the products of conception through decidual necrosis, myometrial contractions, and cervical softening., When administered in the early stages of pregnancy, mifepristone causes decidual breakdown by blockade of uterine progesterone receptors. This leads to detachment of the blastocyte, which decreases hCG production. This in turn causes a decrease in progesterone secretion from the corpus luteum, which further accentuates decidual breakdown. Decreased endogenous progesterone coupled with blockade of progesterone receptors in the uterus increases prostaglandin levels and sensitizes the myometrium to the contractile actions of prostaglandins., In addition, mifepristone promotes uterine contractions and softening of the cervix and sensitizes the myometrium to effects of prostaglandins (e.g., misoprostol) that stimulate uterine contraction and expulsion of the products of conception. In the absence of progesterone, mifepristone acts as a partial progestin agonist. At dosages higher than those used for termination of pregnancy, mifepristone also exhibits antiglucocorticoid activity. The drug also has been shown to have weak antiandrogenic activity. |
Source
|
| Record name | Mifepristone | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00834 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | MIFEPRISTONE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6841 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Yellow powder | |
CAS No. |
84371-65-3 |
Source
|
| Record name | Mifepristone | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=84371-65-3 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Mifepristone [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0084371653 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Mifepristone | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00834 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Mifepristone | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID5023322 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Estra-4,9-dien-3-one, 11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propyn-1-yl)-, (11β,17β) | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.127.911 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | MIFEPRISTONE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/320T6RNW1F | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | MIFEPRISTONE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6841 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Mifepristone | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014972 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
191-196 °C, 150 °C, 191 - 196 °C |
Source
|
| Record name | Mifepristone | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00834 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | MIFEPRISTONE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6841 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Mifepristone | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014972 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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