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 ID: 570
• Molecular Formular: C23H31NO7
• Molecular Mass: 433.49474
• Monoisotopic Mass: 433.21005234
• 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

NAMES AND DATABASE IDS

Names

• IUPAC name: 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 Traditional name: 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
• Brand Name: CellCept; Munoloc
• Synonyms: (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

Database IDs

• CAS Number: 128794-94-5
• PubChem SID: 160964033; 46505626
• PubChem CID: 5281078

CALCULATED PROPERTIES

JChem

• Acid pKa: 9.758892
• H Acceptors: 6
• H Donor: 1
• LogD (pH = 5.5): 2.6996782
• LogD (pH = 7.4): 3.4455073
• Log P: 3.4736357
• Molar Refractivity: 117.0961 cm^3
• Polarizability: 44.90219 Å^3
• Polar Surface Area: 94.53 Å^2
• Rotatable Bonds: 10
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 2.17
• LOG S: -3.66
• Solubility (Water): 9.50e-02 g/l

PROPERTIES

Physical Property

• Solubility: Chloroform; Methanol; Slightly soluble (43 mg/mL at pH 7.4)
• Apperance: White Solid
• Melting Point: 95-96°C
• Hydrophobicity(logP): 2.5

Safety Information

• Storage Condition: -20°C; -20°C Freezer

Pharmacology Properties

• Mechanism of Action: Antiarthritic; Immunosuppressant

Product Information

• Salt Data: Free Base
• Biological Source: Penicillium SP
• Application(s): Used in kidney transplant rejection

DETAILS

DrugBank - DB00688

• 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

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.

Combination Therapy

• Description: Combination therapy of Mycophenolate mofetil and tacrolimus is currently in Phase III clinical trials in patients with Kidney Transplant.

Protocol

• 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.
• Protocol: 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.
• Protocol: 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

• References: [1] Nakanishi T, et al. Int Immunopharmacol. 2010, 10(1), 91-97.
• References: [2] Dehghani F, et al. Neuropathol Appl Neurobiol. 2010, 36(7), 598-611.
• References: [3] Ozgen M, et al. Clin Exp Dermatol. 2012, 37(1), 48-54.
• References: [4] Ebrahimi F, et al. J Neuroinflammation. 2012, 9(1), 89.

InterBioScreen - BB_NC-2566

Penicillium SP

Toronto Research Chemicals - M831450

An immunosuppressant.

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
• Nakanishi T, et al. Int Immunopharmacol. 2010, 10(1), 91-97.
• Dehghani F, et al. Neuropathol Appl Neurobiol. 2010, 36(7), 598-611.
• Ozgen M, et al. Clin Exp Dermatol. 2012, 37(1), 48-54.
• Ebrahimi F, et al. J Neuroinflammation. 2012, 9(1), 89.
• Lee, W.A., et al.: Pharm. Res., 7, 161 (1990)
• Bullingham, R.E.S., et al.: Transplant. Proc., 28, 925 (1990)
• Keown, P.A., et al.: Transplantation, 61, 1029 (1990)
• .
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