Simvastatin
[CAS# 79902-63-9]

Identification

• Classification: API >> Circulatory system medication >> Regulating blood lipids
• Name: Simvastatin
• Synonyms: (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 2,2-dimethyl-butanoate
• Molecular Formula: C₂₅H₃₈O₅
• Molecular Weight: 418.57
• CAS Registry Number: 79902-63-9
• EC Number: 691-267-8
• 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

Properties

• Solubility: 85 mg/mL (DMSO)
• Melting point: 127-132 °C

Safety Data

• Hazard Symbols: GHS07;GHS09 Warning
• Risk Statements: H315-H362-H410
• Safety Statements: P203-P260-P263-P264-P270-P273-P280-P302+P352-P318-P321-P332+P317-P362+P364-P391-P501

Discovery and Applications

Simvastatin is a widely used statin that is effective in lowering cholesterol levels and reducing the risk of cardiovascular disease. Since its approval in the late 1980s, simvastatin has become a cornerstone of lipid-lowering therapy and has had a significant impact on public health by controlling hypercholesterolemia.

The discovery of simvastatin began with studies of the natural compound lovastatin, which was originally isolated from the fungus Aspergillus terreus. Simvastatin was developed by Merck as a semisynthetic derivative designed to improve potency and efficacy. After extensive clinical trials that demonstrated its effectiveness in lowering low-density lipoprotein (LDL) cholesterol, simvastatin was approved by the FDA in 1991.

Simvastatin belongs to the statin class of drugs, which are characterized by their ability to inhibit HMG-CoA reductase, the enzyme responsible for cholesterol synthesis in the liver. Chemically, it is a lactone that is converted in the body to its active form, a hydroxy acid that mimics the substrate of HMG-CoA reductase, thereby competitively inhibiting the enzyme.

Simvastatin works by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway of cholesterol synthesis. This inhibition results in decreased cholesterol production in the liver and increased absorption of LDL cholesterol in the blood, thereby lowering total and LDL cholesterol levels.

Simvastatin is primarily used to treat primary hypercholesterolemia, which is characterized by high levels of LDL cholesterol. It effectively lowers LDL and total cholesterol while modestly raising high-density lipoprotein (HDL) cholesterol. It is also used to treat familial hypercholesterolemia, an inherited disorder that results in extremely high cholesterol levels from an early age.

For patients with existing cardiovascular disease, simvastatin helps reduce the risk of heart attack, stroke, and other complications by stabilizing atherosclerotic plaques and reducing inflammation. For people who are at high risk but do not have cardiovascular disease, simvastatin can reduce the risk of heart disease by controlling cholesterol levels.

For people with diabetes, simvastatin reduces cardiovascular risk, which is critical because diabetes significantly increases the likelihood of heart disease.

Simvastatin has multiple benefits in cholesterol management: it significantly lowers LDL cholesterol, which is essential for preventing cardiovascular disease; it has a well-established safety profile, with most side effects, such as muscle pain and digestive disturbances, being mild and manageable; and it can be used in combination with other lipid-lowering or antihypertensive drugs to enhance the therapeutic effect.

However, simvastatin must be used with caution in patients with liver disease or taking medications that interact with its metabolism, as these medications increase the risk of muscle-related side effects and elevated liver enzymes.

References

1998. Hepatic responses to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase: a comparison of atorvastatin and simvastatin. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1391(1).
DOI: 10.1016/s0005-2760(97)00182-3

1994. Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study. European Heart Journal, 15(2).
DOI: 10.1093/oxfordjournals.eurheartj.a060485

1994. Low-Dose Simvastatin Is a Well-Tolerated and Efficacious Cholesterol-Lowering Agent in Ciclosporin-Treated Kidney Transplant Recipients: Double-Blind, Randomized, Placebo-Controlled Study in 40 Patients. Nephron, 68(1).
DOI: 10.1159/000188088