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Simvastatin

Names

[ CAS No. ]:
79902-63-9

[ Name ]:
Simvastatin

[Synonym ]:
2,2-Dimethylbutanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
Lipex
2,2-Dimethylbutyric Acid 8-Ester with (4R,6R)-6-[2-[(1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-Hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
Velostatin
(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate
ZOCOR
(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate
Simvotin
Corolin
MFCD00072007
Cholestat
Butanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
Colemin
Coledis
Simvastatin
EINECS 404-520-2
Kolestevan
Lipovas
Nor-Vastina
Zocord
Liponorm
Lipinorm
Modutrol
[1S-[1a,3a,7b,8b(2S*,4S*),8ab]]-2,2-Dimethylbutanoic Acid1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl Ester
Eucor
simcor
Denan
simvasterol
Rechol
Valemia
Sivastin

Biological Activity

[Description]:

Simvastatin (MK 733) is a competitive inhibitor of HMG-CoA reductase with a Ki of 0.2 nM.

[Related Catalog]:

Signaling Pathways >> Autophagy >> Autophagy
Signaling Pathways >> Metabolic Enzyme/Protease >> HMG-CoA Reductase (HMGCR)
Signaling Pathways >> Autophagy >> Mitophagy
Research Areas >> Cardiovascular Disease

[Target]

Ki: 0.2 nM (HMG-CoA reductase)[1]


[In Vitro]

Simvastatin needs to be activated by NaOH in EtOH treatment before use for cell assay. Simvastatin suppresses cholesterol synthesis in mouse L-M cell, rat H4II E cell, and human Hep G2 cell with IC50s of 19.3 nM, 13.3 nM and 15.6 nM, respectively[1]. Simvastatin causes a dose-dependent increase in serine 473 phosphorylation of Akt within 30 minutes, with maximal phosphorylation occurring at 1.0 µM. Simvastatin (1.0 μM) enhances phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS), inhibits serum-free media undergo apoptosis and accelerates vascular structure formation[2]. Simvastatin shows anti-inflammatory effects, reduces anti-CD3/anti-CD28 antibody-stimulated proliferation of PB-derived mononuclear cells and synovial fluid cells from rheumatoid arthritis blood, as well as IFN-γ release at 10 μM. Simvastatin (10 μM) also blocks cell-mediated macrophage TNF-γ release induced via cognate interactions by appr 30%[3]. Simvastatin (5 μM) significantly reduces the expression of ABCA1 in astrocytes and neuroblastoma cells, the expression of apolipoprotein E in astrocytes, and increases cyclin-dependent kinase 5 and glycogen synthase kinase 3β expression in SK-N-SH cells[7].

[In Vivo]

Simvastatin suppresses the conversion of radiolabeled acetate to cholesterol with an IC50 of 0.2 mg/kg via p.o. administration[1]. Simvastatin (4 mg/day, p.o. for 13 weeks) returns the cholesterol-induced increases in total cholesterol, LDL-cholesterol and HDL-cholesterol to normal level in rabbits fed an atherogenci cholesterol-rich diet[4]. Simvastatin (6 mg/kg) increases LDL receptor-dependent binding and the number of hepatic LDL receptors in rabbits fed a diet containing 0.25% cholesterol[5]. Simvastatin affects inflammation independent of its effect on plasma cholesterol level. Simvastatin (20 mg/kg/day) causes a 1.3-fold less macrophage content in lesions, and 2-fold less vascular cell adhesion molecule-1, interleukin-1beta, and tissue factor expression, companied by a 2.1-fold increases in lesional smooth muscle cell and collagen content in cynomolgus monkeys fed an atherogenic diet[6].

[Kinase Assay]

For assessment of Akt protein kinase activity in vitro, substrate (2 μg histone H2B or 25 μg eNOS peptide) is incubated with Akt immunoprecipitated from cell lysate using goat polyclonal anti-Akt1 antibody. Kinase reactions are initiated following the addition of Simvastatin to a final concentration of ATP (50 μM) containing 10 μCi of 32P-γATP, dithiotreitol (1 mM), HEPES buffer (20 mM, pH 7.4), MnCl2 (10 mM), MgCl2 (10 mM). After incubation for 30 min at 30°C, phosphorylated histone H2B is visualized after SDS-PAGE (15%) and autoradiography. To estimate the extent of 32P incorporation into eNOS peptides, each reaction mixture is measured by spotting onto phosphocellulose disc filter and the amount of phosphate incorporated is measured by Cerenkov counting. The wild-type peptide sequence is 1174-RIRTQSFSLQERHLRGAVPWA-1194, and the mutant eNOS peptide is identical except that serine 1179 is substituted by alanine[3].

[Cell Assay]

Primary human astrocytes from four different donors are prepared from tissue obtained from legally aborted fetuses. Primary human astrocytes and SK-N-SH neuroblastoma cell line (ATCC) are plated on 6-well plates and grown in DMEM supplemented with 5% or 8% fetal calf serum, respectively, at 37°C, 5% CO2 until 80% confluent. For measurement of gene expression levels at baseline, cells are just washed and RNA is prepared and assayed as outlined below. Baseline gene expression levels in astrocytes are measured in primary human astrocytes obtained from two donors. For experimental purposes, cells are incubated under serum-free conditions. Primary human astrocytes are obtained from four donors. Based on preliminary time-dependent studies, 48-h incubation is used for all of experiments. Based on the dose-response studies, a majority of our experiments are conducted using the following concentrations of active compounds: Simvastatin at 5 μM, pravastatin at 10 μM, mevalonate at 50 μM, and GGPP and FPP at 10 μM. Following incubation, cells are extensively washed to remove dead cells and cell debris and prepared for further analyses[7].

[Animal admin]

Monkeys[1] Thirty-nine adult male cynomolgus monkeys are initially fed a moderately atherogenic diet containing 0.28 mg cholesterol per calorie of diet, with 16.7% from protein, 45.1% from lipids, and 38.1% from carbohydrates. After consuming the atherogenic diet for 3 months, the monkeys are divided into 3 groups (n=13 each) that are equivalent in their total plasma cholesterol (TPC), LDL-C, and HDL cholesterol (HDL-C) concentrations; these groups consume the atherogenic diet and receive statin (or control) treatment for an additional 15 months. Control monkeys are fed the atherogenic diet with no added statins. Prava-treated monkeys have 40 mg Prava/kg body wt per day added to the atherogenic diet. Simvastatin-treated monkeys consumed 20 mg Simvastatin/kg body wt per day[1].

[References]

[1]. Slater, E.E., et al. Mechanism of action and biological profile of HMG CoA reductase inhibitors. A new therapeutic alternative. Drugs, 1988. 36 Suppl 3: p. 72-82.

[2]. Kureishi, Y., et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med, 2000. 6(9): p. 1004-10.

[3]. Leung BP, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003 Feb 1;170(3):1524-30.

[4]. Kobayashi M, et al. Preventive effect of MK-733 (simvastatin), an inhibitor of HMG-CoA reductase, on hypercholesterolemia and atherosclerosis induced by cholesterol feeding in rabbits. Jpn J Pharmacol. 1989 Jan;49(1):125-33.

[5]. Ishida F, et al. Comparative effects of simvastatin (MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by cholesterol feeding in rabbits. Biochim Biophys Acta. 1990 Feb 23;1042(3):365-73.

[6]. Sukhova GK, et al. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler Thromb Vasc Biol. 2002 Sep 1;22(9):1452-8.

[7]. Weijiang Dong, et al. Differential effects of simvastatin and pravastatin on expression of Alzheimer’s disease-related genes in human astrocytes and neuronal cells. J Lipid Res. 2009 Oct; 50(10): 2095-2102.

[8]. Liu Z, et al. Pretreatment Donors after Circulatory Death with Simvastatin Alleviates Liver Ischemia Reperfusion Injury through a KLF2-Dependent Mechanism in Rat. Oxid Med Cell Longev. 2017;2017:3861914.


[Related Small Molecules]

3-Methyladenine | SB203580 | U0126-EtOH | Acadesine (AICAR) | Brefeldin A | 17-AAG | Resveratrol | Melatonine | Curcumin | Salinomycin | ABT-737 | Quercetin | Celastrol | Hemin | Torkinib (PP242)

Chemical & Physical Properties

[ Density]:
1.1±0.1 g/cm3

[ Boiling Point ]:
564.9±50.0 °C at 760 mmHg

[ Melting Point ]:
139 °C

[ Molecular Formula ]:
C25H38O5

[ Molecular Weight ]:
418.566

[ Flash Point ]:
184.8±23.6 °C

[ Exact Mass ]:
418.271912

[ PSA ]:
72.83000

[ LogP ]:
4.41

[ Vapour Pressure ]:
0.0±3.5 mmHg at 25°C

[ Index of Refraction ]:
1.530

MSDS

Toxicological Information

CHEMICAL IDENTIFICATION

RTECS NUMBER :
EK7798000
CHEMICAL NAME :
Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro- 4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester, (1S-(1-alpha,3-alpha,7- beta,8-beta(2S*,4S*),8a-beta))-
CAS REGISTRY NUMBER :
79902-63-9
LAST UPDATED :
199612
DATA ITEMS CITED :
15
MOLECULAR FORMULA :
C25-H38-O5
MOLECULAR WEIGHT :
418.63

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - woman
DOSE/DURATION :
2800 ug/kg/7D-I
TOXIC EFFECTS :
Behavioral - somnolence (general depressed activity) Liver - jaundice (or hyperbilirubinemia) hepatocellular Liver - liver function tests impaired
REFERENCE :
MJAUAJ Medical Journal of Australia. (Australasian Medical Pub. Co. Ltd., 71-79 Arundel St., Glebe, N.S.W., Australia) V.1- 1914- Volume(issue)/page/year: 155,61,1991
TYPE OF TEST :
LDLo - Lowest published lethal dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - woman
DOSE/DURATION :
108 mg/kg/77W-I
TOXIC EFFECTS :
Behavioral - muscle weakness Lungs, Thorax, or Respiration - acute pulmonary edema Skin and Appendages - dermatitis, other (after systemic exposure)
REFERENCE :
ANZJB8 Australian and New Zealand Journal of Medicine. (Modern Medicine of Australia Pty., Ltd., 100 Pacific Highway, North Sydney, 2060, Australia) V.1- 1971- Volume(issue)/page/year: 25,745,1995
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
4438 mg/kg
TOXIC EFFECTS :
Behavioral - altered sleep time (including change in righting reflex) Behavioral - somnolence (general depressed activity) Gastrointestinal - other changes
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,95,1990
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
705 mg/kg
TOXIC EFFECTS :
Sense Organs and Special Senses (Eye) - lacrimation Behavioral - muscle contraction or spasticity
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,95,1990
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
672 mg/kg
TOXIC EFFECTS :
Behavioral - muscle contraction or spasticity
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,95,1990
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
3 gm/kg
TOXIC EFFECTS :
Behavioral - altered sleep time (including change in righting reflex) Behavioral - somnolence (general depressed activity) Gastrointestinal - other changes
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,95,1990
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
798 mg/kg
TOXIC EFFECTS :
Sense Organs and Special Senses (Eye) - lacrimation Behavioral - muscle contraction or spasticity
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,95,1990
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
1009 mg/kg
TOXIC EFFECTS :
Behavioral - muscle contraction or spasticity
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,95,1990
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Mammal - dog
DOSE/DURATION :
>5 gm/kg
TOXIC EFFECTS :
Gastrointestinal - hypermotility, diarrhea Gastrointestinal - nausea or vomiting
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,95,1990 ** OTHER MULTIPLE DOSE TOXICITY DATA **
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
9275 mg/kg/53W-I
TOXIC EFFECTS :
Brain and Coverings - changes in brain weight Liver - changes in liver weight Endocrine - changes in thyroid weight
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,103,1990
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
17640 mg/kg/14W-I
TOXIC EFFECTS :
Blood - changes in bone marrow (not otherwise specified) Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases Related to Chronic Data - death
REFERENCE :
YKYUA6 Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- Volume(issue)/page/year: 43,259,1992
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - hamster
DOSE/DURATION :
120 mg/kg/12D-I
TOXIC EFFECTS :
Liver - hepatitis (hepatocellular necrosis), zonal Nutritional and Gross Metabolic - weight loss or decreased weight gain Related to Chronic Data - death
REFERENCE :
PHTOEH Pharmacology and Toxicology (Copenhagen). (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) V.60- 1987- Volume(issue)/page/year: 77,391,1995 ** REPRODUCTIVE DATA **
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
300 mg/kg
SEX/DURATION :
female 6-17 day(s) after conception
TOXIC EFFECTS :
Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,143,1990
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
480 mg/kg
SEX/DURATION :
female 6-17 day(s) after conception
TOXIC EFFECTS :
Reproductive - Effects on Newborn - behavioral
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,143,1990
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
350 mg/kg
SEX/DURATION :
female 15-21 day(s) after conception lactating female 21 day(s) post-birth
TOXIC EFFECTS :
Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 39,169,1990

Safety Information

[ Personal Protective Equipment ]:
Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter

[ Hazard Codes ]:
Xi: Irritant;

[ Risk Phrases ]:
R36/37/38

[ Safety Phrases ]:
26-36

[ RIDADR ]:
3077

[ RTECS ]:
EK7798000

[ Packaging Group ]:
III

[ Hazard Class ]:
9

Synthetic Route

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