Description
Simvastatin is an once-daily hypolipemic, an analog of lovastatin indicated for the
treatment of atherosclerosis. In patients with Type IN or IIB hypercholesterolemia,
simvastatin reportedly produces significant reductions in total serum cholesterol, LDL,
mglycerides and apolipoprotein-B, while HDL and apolipoprotein-A levels are increased.
Definition
ChEBI: A carbobicyclic compound that is lovastatin in which the 2-methylbutyrate ester moiety has been replaced by a 2,2-dimethylbutyrate ester group. It is used as a cholesterol-lowering and anti-cardiovascular disease drug.
Manufacturing Process
A suspension of Lovastatin (350 g, 0.865 mmol), phenylboronic acid (110.8 g,
0.909 mmol) and toluene (1.75 L) was heated under a nitrogen atmosphere
at 100-105°C for 55 min. The water was separated from the reaction mixture.
The solution was cooled and 1.39 L of toluene was removed by vacuum
distillation at 40-50°C. The concentrated solution was treated with hexanes
(3.15 L) at 40-50°C. The resulting suspension was cooled to 0-5C for 2 hours
and the product was filtered and washed with hexanes (350 mL). The product
was dried at 35-40°C under vacuum to provide 427.9 g (37%) of lovastatin
phenylboronate at >99% purity by HPLC.
A 2 L 3-necked flask was charged with pyrrolidine (56 mL, 0.67 mol) and dry
THF (453 g) under a nitrogen atmosphere. n-Butyl lithium (419 mL, 1.6 M
hexane solution, 0.67 mol) was added dropwise at -20°C over a period of 1
hour. The solution was maintained at this temperature for 30 min and then
cooled to -55°C. A solution of lovastatin phenylboronate (101.7 g, 0.20 mol)
in 274.7 g of THF was cooled to -50°C and then added to the cold lithium
pyrrolidide solution at a rate such that the internal temperature was between
-50°-55°C during the addition. The mixture was held at this temperature for 4
hours and then methyl iodide (116.4 g, 0.82 mol) was added at a
temperature below -55°C. The reaction was stirred for 13 hours at -20°C and
then quenched with 500 mL of 2 M HCl at a temperature below 0°C. After
warming to 20°C, the layers were separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were washed with
5% NaHSO3 solution and deionized water. The solution was filtered through a
Celite pad and concentrated to yield 102.8 g (98.4%) of crude Simvastatin
phenylboronate at >95% purity by HPLC. A portion of the above material
(50.0 g) was charged into a nitrogen purged flask with acetonitrile (100 mL).
The suspension was heated at 110°C for 3 hours and then cooled to - 10°C for 1 hour. The product was filtered and washed with 25 mL of acetonitrile and
dried under vacuum to provide 43.7 g of Simvastatin phenylboronate at >99%
purity by HPLC.
A suspension of simvastatin phenylboronate (30.0 g) and 1,3-propanediol
(450 mL) was heated at 105-107°C at 0.2 mm Hg. After 1 hour, 182 mL of
distillate was collected and the reaction was cooled to 20-25°C. Deionized
water (270 mL) was added and toluene (3 times 75 mL) was used to extract
the mixture. The combined toluene layers were washed with water (60 mL).
The organic solution was heated at reflux for 1 hour and water was
azeotropically removed. The solution was concentrated to a final volume of 24
mL under vacuum at 48-50°C. To the concentrated solution was added
hexanes (215 mL) over 10 min. The resulting slurry was cooled to 0-5°C and
filtered. The crude Simvastatin was washed at 0-5°C with hexanes and dried
under vacuum to yield 21.0 g (88%) of Simvastatin.
Brand name
Zocor (Merck);Zocord.
Therapeutic Function
Antihyperlipidemic
General Description
Simvastatin, 2,2-dimethyl butanoic acid,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2-pyran-2-yl)ethyl]-1-naphthalenyl ester(Zocor), is an analog of lovastatin. These two drugs havemany similar properties. Both drugs, in the prodrug form,reach the liver unchanged after oral administration, wherethey undergo extensive metabolism to several open-ring hydroxyacids, including the active -hydroxy acids. They arealso highly bound to plasma proteins. These actions makethe bioavailability of simvastatin rather poor but better thanthat of lovastatin, which has been estimated to be 5%.
Biological Activity
HMG-CoA reductase inhibitor; decreases levels of low density lipoprotein. Has multiple biological effects including bone formation stimulation, inhibition of smooth muscle cell proliferation and migration, and anticancer and anti-inflammatory activity.
Biochem/physiol Actions
Simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early step in cholesterol biosynthesis. It is used in the treatment of hypercholesterolemia, as it reduces levels of low-density lipoproteins and triglycerides, and raises high-density lipoprotein levels. Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, and can be activated prior to use with NaOH in EtOH treatment. It is a synthetic analog of lovastatin (Cat. No. M2147).
Clinical Use
HMG CoA reductase inhibitor:
Primary hypercholesterolaemia
target
TNF-α | NF-kB | MMP(e.g.TIMP) | p65 | JNK | Beta Amyloid | TGF-β/Smad | NO | NOS | STAT | IFN-γ
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: increased risk of myopathy with
amiodarone - do not exceed 20 mg of simvastatin1
;
increased risk of myopathy with dronedarone.
Antibacterials: increased risk of myopathy with
clarithromycin, daptomycin, erythromycin and
fusidic acid - avoid; possibly increased myopathy
with azithromycin; concentration possibly reduced
by rifampicin.
Anticoagulants: effects of coumarins enhanced.
Antiepileptics: concentration reduced by
carbamazepine and eslicarbazepine.
Antifungals: increased risk of myopathy
with fluconazole, itraconazole, posaconazole,
ketoconazole, voriconazole and possibly miconazole
- avoid; possibly increased risk of myopathy with
imidazoles.
Antivirals: increased risk of myopathy with
atazanavir, indinavir, lopinavir, ritonavir or saquinavir
and possibly fosamprenavir, lopinavir or tipranavir -
avoid; concentration reduced by efavirenz; avoid with
boceprevir, dasabuvir, ombitasvir, paritaprevir and
telaprevir; possible increased risk of myopathy with
ledipasvir - reduce simvastatin dose; concentration
increased by simeprevir - consider reducing
simvastatin dose.
Calcium-channel blockers: increased risk of
myopathy with verapamil, diltiazem and amlodipine
- do not exceed 20 mg of simvastatin.1
Ciclosporin: increased risk of myopathy - avoid.1
Cobicistat: avoid with simvastatin.
Colchicine: possible increased risk of myopathy.
Grapefruit: increased risk of myopathy - avoid.
Hormone antagonists: possibly increased risk of
myopathy with danazol - avoid.1
Lipid-lowering agents: increased risk of myopathy
with fibrates - do not exceed 10 mg of simvastatin
except with fenofibrate1
; gemfibrozil - avoid;
concentration increased by lomitapide - do not
exceed 40 mg of simvastatin; increased risk of
myopathy with nicotinic acid.
Ranolazine: concentration increased by ranolazine,
maximum dose of simvastatin is 20 mg.
Ticagrelor: concentration of simvastatin increased;
maximum dose of simvastatin is 40 mg
Metabolism
Simvastatin is absorbed from the gastrointestinal tract
and must be hydrolysed to its active β-hydroxyacid form.
Other active metabolites have been detected and several
inactive metabolites are also formed. Simvastatin is a
substrate for the cytochrome P450 isoenzyme CYP3A4
and undergoes extensive first-pass metabolism in the
liver, its primary site of action. Less than 5% of an oral
dose has been reported to reach the circulation as active
metabolites.
Simvastatin is mainly excreted in the faeces via the bile
as metabolites. About 10-15% is recovered in the urine,
mainly in inactive forms.
storage
Desiccate at -20°C
References
References/Citations
1) Merck 14:8539
2) Hancock et al. (1989), All ras proteins are polyisoprenylated but only some are palmitoylated; Cell, 57 1167
3) Ose et al. (2000), Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group Clin. Cardiol. 23 39
4) Matsuzaka et al. (2016) Characterization and functional analysis of extracellular vesicles and muscle-abundant miRNA in C2C12 myocytes and Mdx mice; PLoS One 11(12) e0167811 [Focus Biomolecules Citation]
