Chemical Property of Simvastatin
Chemical Property:
- Appearance/Colour:White powder
- Vapor Pressure:4.12E-15mmHg at 25°C
- Melting Point:139 °C
- Refractive Index:1.53
- Boiling Point:564.9 °C at 760 mmHg
- PKA:13.49±0.40(Predicted)
- Flash Point:184.8 °C
- PSA：72.83000
- Density:1.11 g/cm3
- LogP:4.58560
- Storage Temp.:0-6°C
- Solubility.:DMSO: ≥20mg/mL
- XLogP3:4.7
- Hydrogen Bond Donor Count:1
- Hydrogen Bond Acceptor Count:5
- Rotatable Bond Count:7
- Exact Mass:418.27192431
- Heavy Atom Count:30
- Complexity:706
- Purity/Quality:
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99% *data from raw suppliers
Simvastatin *data from reagent suppliers
Safty Information:
- Pictogram(s):
Xi
- Hazard Codes:Xi
- Statements:
36/37/38
- Safety Statements:
26-36-24/25
- MSDS Files:
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SDS file from LookChem
Useful:
- Drug Classes:Antilipemic Agents
- Canonical SMILES:CCC(C)(C)C(=O)OC1CC(C=C2C1C(C(C=C2)C)CCC3CC(CC(=O)O3)O)C
- Isomeric SMILES:CCC(C)(C)C(=O)O[C@H]1C[C@H](C=C2[C@H]1[C@H]([C@H](C=C2)C)CC[C@@H]3C[C@H](CC(=O)O3)O)C
- Recent ClinicalTrials:Multi-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis
- Recent EU Clinical Trials:Randomized phase 2 study of Valproic acid combinEd with Simvastatin and gemcitabine/nab-paclitaxel-based regimens in untreated metastatic Pancreatic Adenocarcinoma patients (The VESPA trial)
- Recent NIPH Clinical Trials:Study of the Effects of eicosapentaenoic acid on diabetic atherosclerotic lesion
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Discovery and Development
In the 1970s, Japanese microbiologist Akira Endo discovered natural products, including ML236B (compactin), with potent inhibitory effects on HMG-CoA reductase, a key enzyme in cholesterol synthesis, from a fermentation broth of Penicillium citrinum.
Simvastatin was the second statin used clinically, following lovastatin. It was approved for marketing in Sweden in 1988 and subsequently worldwide.
Simvastatin was patented by Merck in 1980 and came into medical use in 1992.
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Medical Uses
Simvastatin is a member of the statin family of drugs used to treat dyslipidemia in patients with elevated cholesterol by inhibiting HMG-CoA reductase, which is a critical step in cholesterol biogenesis.
Simvastatin, an FDA-approved drug for hypercholesterolemia, has shown therapeutic effects in treating leiomyomas. Previous studies have shown that simvastatin reduces leiomyoma growth, inhibits mitogen-activated protein kinase signaling, induces apoptosis, and alters extracellular matrix protein expression and mechanotransduction in leiomyoma cells. Large dataset analysis has demonstrated the benefit of simvastatin in several tumors, including uterine leiomyoma.
Anticancer Activities: Simvastatin, a type of statin, has been rediscovered for its anticancer activities, influencing the proliferation, migration, and survival of cancer cells. In vitro and in vivo experiments, as well as cohort studies, have demonstrated the antitumor effects of simvastatin by influencing inflammatory and oxidative stress-related tumorigenesis. Hydrophilic statins, like pravastatin and rosuvastatin, accumulate in the liver, while hydrophobic statins, such as simvastatin, are distributed to various tissues, explaining their frequent use.
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Market Value
Simvastatin is marketed by Merck as Zocor and is the second-best-selling drug in the United States, with annual sales exceeding $5 billion.
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Synthesis of Simvastatin
Simvastatin is synthesized through various chemical processes, including dehydration, Michael's addition of N-benzyl hydroxylamine, cyclization, and reduction with sodium cyanoborohydride.
Currently, two semisynthetic processes are widely used to synthesize simvastatin starting from lovastatin . One commonly adapted process starts with the hydrolysis of lovastatin to yield the key intermediate monacolin J, followed by the lactonization of the acid to protect the C11 hydroxyl group and trimethylsilylation protection of the C13 hydroxyl. The protected monacolin J is then subjected to acylation by 伪-dimethylbutyryl chloride to yield the protected form of simvastatin, which is subsequently deprotected to yield simvastatin.
In previous studies, a one-step, whole-cell biocatalytic process has been developed for the synthesis of simvastatin from monacolin J. Escherichia coli overexpressing the acyltransferase LovD achieves >99% conversion of monacolin J to simvastatin without chemical protection steps. The process was scaled up for gram-scale synthesis, and simvastatin was readily purified from the fermentation broth with high recovery and purity.
