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128794-94-5 分子结构
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2-(morpholin-4-yl)ethyl (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate

ChemBase编号:570
分子式:C23H31NO7
平均质量:433.49474
单一同位素质量:433.21005234
SMILES和InChIs

SMILES:
O1CCN(CC1)CCOC(=O)CC/C(=C/Cc1c(OC)c(c2c(c1O)C(=O)OC2)C)/C
Canonical SMILES:
COc1c(C/C=C(/CCC(=O)OCCN2CCOCC2)\C)c(O)c2c(c1C)COC2=O
InChI:
InChI=1S/C23H31NO7/c1-15(5-7-19(25)30-13-10-24-8-11-29-12-9-24)4-6-17-21(26)20-18(14-31-23(20)27)16(2)22(17)28-3/h4,26H,5-14H2,1-3H3/b15-4+
InChIKey:
RTGDFNSFWBGLEC-SYZQJQIISA-N

引用这个纪录

CBID:570 http://www.chembase.cn/molecule-570.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
2-(morpholin-4-yl)ethyl (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate
IUPAC传统名
2-(morpholin-4-yl)ethyl (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate
mycophenolate mofetil
商标名
CellCept
Munoloc
别名
(4E)-6-(1,3-Dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)4-hexenoic Acid 4-methyl-2-(4-morpholinyl)ethyl Ester
Mycophenolic Acid 2-(4-Morpholinyl)ethyl Ester
2-(4-Morpholinyl)ethyl ester
Mycophenolate mofetil
Mycophenylate mofetil
Mycophenolate mofetil
(E)-2-morpholinoethyl 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate
CellCept
RS 61443
TM-MMF
CAS号
128794-94-5
PubChem SID
160964033
46505626
PubChem CID
5281078

理论计算性质

理论计算性质

JChem ALOGPS 2.1
Acid pKa 9.758892  质子受体
质子供体 LogD (pH = 5.5) 2.6996782 
LogD (pH = 7.4) 3.4455073  Log P 3.4736357 
摩尔折射率 117.0961 cm3 极化性 44.90219 Å3
极化表面积 94.53 Å2 可自由旋转的化学键 10 
里宾斯基五规则 true 
Log P 2.17  LOG S -3.66 
溶解度 9.50e-02 g/l 

分子性质

分子性质

理化性质 安全信息 药理学性质 产品相关信息 生物活性(PubChem)
溶解度
Chloroform expand 查看数据来源
Methanol expand 查看数据来源
Slightly soluble (43 mg/mL at pH 7.4) expand 查看数据来源
外观
White Solid expand 查看数据来源
熔点
95-96°C expand 查看数据来源
疏水性(logP)
2.5 expand 查看数据来源
保存条件
-20°C expand 查看数据来源
-20°C Freezer expand 查看数据来源
MSDS下载
下载链接 expand 查看数据来源
生物活性机理
Antiarthritic expand 查看数据来源
Immunosuppressant expand 查看数据来源
成盐信息
Free Base expand 查看数据来源
质检报告
下载链接 expand 查看数据来源
生物来源
Penicillium SP expand 查看数据来源
应用领域
Used in kidney transplant rejection expand 查看数据来源

详细说明

详细说明

DrugBank DrugBank Selleck Chemicals Selleck Chemicals InterBioScreen InterBioScreen TRC TRC
DrugBank -  DB00688 external link
Item Information
Drug Groups approved; investigational
Description Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent, inosine monophosphate dehydrogenase (IMPDH) inhibitor.
Indication For the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.
Pharmacology Mycophenolate mofetil is a prodrug of mycophenolic acid, an antibiotic substance derived from Penicillium stoloniferum. It blocks de novo biosynthesis of purine nucleotides by inhibition of the enzyme inosine monophosphate dehydrogenase. Mycophenolic acid is important because of its selective effects on the immune system. It prevents the proliferation of T-cells, lymphocytes, and the formation of antibodies from B-cells. It also may inhibit recruitment of leukocytes to inflammatory sites.
Toxicity Oral (LD50): Acute: 352 mg/kg [Rat], 1000 mg/kg [Mouse], and >6000 mg/kg [Rabbit]. Possible signs and symptoms of acute overdose could include the following: hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea and vomiting, and dyspepsia.
Affected Organisms
Humans and other mammals
Biotransformation Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.
Absorption Rapidly absorbed following oral administration. In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. Food (27 g fat, 650 calories) has no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil.
Half Life The mean elimination half-life for mycophenolic acid (the active metabolite) ranges from 8-16 hours, while that of the MPAG metabolite ranges from 13-17 hours.
Protein Binding MPA (the active metabolite), at clinically relevant concentrations, is over 98% bound to plasma albumin.
Elimination Negligible amount of drug is excreted as MPA (< 1% of dose) in the urine. Most (about 87%) of the administered dose is excreted in the urine as MPAG.
Distribution * 3.6 ±1.5 L/kg [intravenous]
* 4 ±1.2 L/kg [oral administration]
Clearance * 193 +/- 48 mL/min [following oral administration]
References
Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, Taylor RS: Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess. 2005 May;9(21):1-179, iii-iv. [Pubmed]
External Links
Wikipedia
RxList
Drugs.com
Selleck Chemicals -  S1501 external link
Research Area
Description Immunology
Biological Activity
Description Mycophenolate mofetil is a non-competitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase I/II with IC50 of 39 nM and 27 nM, respectively.
Targets Inosine monophosphate dehydrogenase I Inosine monophosphate dehydrogenase II
IC50 39 nM 27 nM [1]
In Vitro Mycophenolate mofetil is an ester prodrug of the active immunosuppressant mycophenolic acid (MPA). The latter shows a noncompetitive, selective and reversible inhibition activity against inosine monophosphate dehydrogenase type I/II with IC50 of 39 nM and 27 nM, respectively. Moreover, MPA also produces the concentration-dependent inhibition of proliferation of ConA-stimulated T cells, LPS-stimulated B cells and alloantigen-specific T cells with IC50 of 100 nM, 120 nM, and 51 nM, respectively. [1] Mycophenolate mofetil with high concentration of 10 μg/mL induces a strong apoptosis in microglial cell cultures and increases the number of activated caspase-3 immunoreactive apoptotic cells. In addition, Mycophenolate mofetil (1 μg/mL) strongly inhibits proliferation of both microglial cells and astrocytes. [2] A recent study shows that Mycophenolate mofetil significantly attenuates the extent of neuronal cell death of organotypic hippocampal slice cultures after neuronal injury in a time-dependent manner. [4]
In Vivo In an ACI-to-Lewis rat heterotopic cardiac transplant model, treatment of Mycophenolate mofetil at doses of 20 mg/kg and 40 mg/kg leads to a prolongation of graft survival, with median survival time (MST) of 14.5 days and 18.5 days, respectively. [1] In bleomycin (BLM)-induced scleroderma mouse model, Mycophenolate mofetil reduces inflammatory-cell infiltration, tissue hydroxyproline content and dermal thickness. [3]
Clinical Trials Mycophenolate mofetil is currently in Phase II clinical trials in patients with Allogeneic Blood and Marrow Transplantation (BMT) Graft Versus Host Disease.
Features
Combination Therapy
Description Combination therapy of Mycophenolate mofetil and tacrolimus is currently in Phase III clinical trials in patients with Kidney Transplant.
Protocol
Kinase Assay [1]
IMP dehydrogenase Types I and II enzymatic activity IMP dehydrogenase Types I and II are purified from E. coli expressing human enzymes. The assay is performed using a flat bottom, UV-transparent 96-well plate. The final 200 μL reaction mixture contained 0.1 M Tris, 0.1 M KCl, 3 mM EDTA pH 8.0, 2 mM DTT, and 40 nM of either IMP dehydrogenase Type I or Type II. The reaction is initiated by adding 400 μM NAD and 400 μM IMP, followed by incubation at 37 °C for 2.5 hours. The reaction rate of the conversion of NAD to NADH is then measured based on the increase in absorbance at 340 nm. The assays are also performed in the presence of 50% human serum to estimate serum protein binding by different IMP dehydrogenase inhibitors.
Cell Assay [1]
Cell Lines ConA-stimulated T cells and LPS-stimulated B cells
Concentrations 0 to 10 μM
Incubation Time 48 hours
Methods The spleens of male Lewis rats aged 8 weeks are aseptically removed and teased into single-cell suspensions, and the resulting splenocytes are suspended in RPMI1640 medium containing 10% fetal calf serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. Assays are performed in flat-bottomed microtiter plates, with each well containing 150000 splenocytes in a total volume of 100 μL. Splenocytes are incubated in medium containing either 1 μg/mL Concanavalin A (ConA) or lipopolysaccharide (LPS) as T or B cell mitogen, respectively, along with various concentrations of MPA at 37 °C for 48 hours in a humidified atmosphere of 5% CO2–95% air. During the final 6 hours of incubation, cells are pulsed with 1 μCi of 3H-thymidine/well, and harvested onto pressed fiberglass in a cell harvester. The uptake of 3H-thymidine by proliferating cells is measured using a liquid scintillation counter. The in vitro immune response of alloantigen-specific T cells is evaluated as a proliferation response using one-way mixed lymphocyte reaction assay. Mesenteric lymph nodes cells from male Lewis rats aged 8 weeks and splenocytes from male ACI rats aged 8 weeks are used as responder and stimulator cells, respectively. Single-cell suspensions are prepared, and the responder cells are cultured with irradiated (20 Gy) stimulator cells in RPMI1640 supplemented with 10% fetal calf serum, 100 U/mL penicillin and 100 μg/mL streptomycin, in 96-well plates (U-bottom) and in the presence of various concentrations of MPA (total volume: 200 μL, 37 °C, 5% CO2 humidified atmosphere, 72 hours). As a negative control, responder cells are cultured with irradiated splenocytes of Lewis rats. The cell proliferation is quantified by the uptake of 3H-thymidine.
Animal Study [1]
Animal Models Lewis rats with abdominal vascularized heterotopic cardiac transplantation.
Formulation Mycophenolate mofetil is dissolved in 0.5% methylcellulose water.
Doses ≤40 mg/kg
Administration Administered via i.v.
References
[1] Nakanishi T, et al. Int Immunopharmacol. 2010, 10(1), 91-97.
[2] Dehghani F, et al. Neuropathol Appl Neurobiol. 2010, 36(7), 598-611.
[3] Ozgen M, et al. Clin Exp Dermatol. 2012, 37(1), 48-54.
[4] Ebrahimi F, et al. J Neuroinflammation. 2012, 9(1), 89.
InterBioScreen -  BB_NC-2566 external link
Penicillium SP
Toronto Research Chemicals -  M831450 external link
An immunosuppressant.

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参考文献

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