Ezetimibe
[CAS# 163222-33-1]

Identification

• Classification: API >> Circulatory system medication >> Anti-atherosclerosis
• Name: Ezetimibe
• Synonyms: 1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-hydroxyphenyl)-azetidin-2-one
• Molecular Formula: C₂₄H₂₁F₂NO₃
• Molecular Weight: 409.43
• CAS Registry Number: 163222-33-1
• EC Number: 682-606-0
• SMILES: C1=CC(=CC=C1[C@@H]2[C@H](C(=O)N2C3=CC=C(C=C3)F)CC[C@@H](C4=CC=C(C=C4)F)O)O

Properties

• Solubility: DMSO:82mg/ml, ethanol:82mg/ml, Water: ?5 mg/mL (Expl.)

Safety Data

• Hazard Symbols: GHS09 Warning
• Risk Statements: H410
• Safety Statements: P273-P391-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Reproductive toxicity	Repr.	2	H361
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Skin irritation	Skin Irrit.	2	H315
Acute toxicity	Acute Tox.	4	H302
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	4	H332
Acute toxicity	Acute Tox.	4	H312
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319
Acute hazardous to the aquatic environment	Aquatic Acute	1	H400

Discovery and Applications

Ezetimibe is a medication used primarily to reduce cholesterol levels in the blood, specifically by inhibiting the absorption of cholesterol from the intestines. It is widely used in the treatment of hypercholesterolemia and other conditions related to high cholesterol. Ezetimibe was first approved by the U.S. Food and Drug Administration (FDA) in 2002, and it has since become a common therapeutic option for patients at risk of cardiovascular diseases associated with high cholesterol.

Ezetimibe works by targeting a specific protein in the small intestine known as the Niemann-Pick C1-like 1 (NPC1L1) protein. This protein is involved in the absorption of cholesterol from the digestive tract into the bloodstream. By inhibiting NPC1L1, ezetimibe reduces the amount of cholesterol that enters the bloodstream, thus lowering overall cholesterol levels.

The mechanism of action of ezetimibe is distinct from that of statins, another class of cholesterol-lowering drugs. While statins work by inhibiting the HMG-CoA reductase enzyme, which is responsible for cholesterol synthesis in the liver, ezetimibe acts at the level of the intestine to prevent the absorption of dietary and biliary cholesterol. Because of this, ezetimibe can be used alone or in combination with statins for more effective cholesterol management.

Ezetimibe is typically prescribed as part of a broader strategy to manage lipid levels, which also includes lifestyle changes such as diet modification and regular physical activity. It is particularly useful for individuals who are unable to achieve adequate cholesterol control through statins alone or for those who cannot tolerate statin therapy due to side effects.

In addition to its primary use in lowering cholesterol, ezetimibe has also been studied for its effects in other lipid-related conditions. It has shown promise in reducing the risk of atherosclerotic cardiovascular disease (ASCVD), as lowering cholesterol is directly associated with reducing the development and progression of atherosclerosis (the buildup of fatty deposits in the arteries). Clinical trials have demonstrated that ezetimibe, when combined with statins, can further lower low-density lipoprotein (LDL) cholesterol, often referred to as "bad cholesterol," and improve overall cardiovascular outcomes.

Ezetimibe is typically well-tolerated, with a side effect profile that is relatively mild compared to other lipid-lowering drugs like statins. Some common side effects may include gastrointestinal issues such as abdominal pain, diarrhea, or flatulence. More serious side effects are rare but may include liver enzyme abnormalities, allergic reactions, and muscle pain. Monitoring of liver function and muscle-related symptoms is recommended during treatment, especially when ezetimibe is used in combination with a statin.

The use of ezetimibe is generally considered safe and effective, but it may not be suitable for individuals with certain medical conditions, such as liver disease, or those who are pregnant or breastfeeding. As with any medication, it is important for patients to discuss their medical history and current medications with their healthcare provider before starting ezetimibe therapy.

In summary, ezetimibe is an important cholesterol-lowering drug that works by inhibiting the absorption of cholesterol from the intestine, offering an effective treatment option for patients with hypercholesterolemia. It is often used in combination with statins to enhance the cholesterol-lowering effect, and its use is associated with a relatively mild side effect profile. Ongoing research continues to explore its potential benefits in reducing cardiovascular events and improving long-term health outcomes for patients with elevated cholesterol levels.

References

1998. Discovery of 1-(4-Fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)- hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A Designed, Potent, Orally Active Inhibitor of Cholesterol Absorption. Journal of Medicinal Chemistry, 41(6).
DOI: 10.1021/jm970701f

2005. Long-term safety and, tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: a multicenter, randomized, double-blind, placebo-controlled, 48-week extension study. Clinical Therapeutics, 27(2).
DOI: 10.1016/j.clinthera.2005.02.011

2009. The effects of ezetimibe on LDL-cholesterol: Quantitative or qualitative changes? Atherosclerosis, 204(2).
DOI: 10.1016/j.atherosclerosis.2008.10.005