Bezafibrate

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Bezafibrate
Bezafibrate.svg
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a682711
Routes of
administration
Oral
ATC code
Legal status
Legal status
Identifiers
  • 2-(4-{2-[(4-chlorobenzoyl)amino]ethyl}phenoxy)-2-methylpropanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.050.498 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H20ClNO4
Molar mass 361.82 g·mol−1
3D model (JSmol)
  • O=C(c1ccc(Cl)cc1)NCCc2ccc(OC(C(=O)O)(C)C)cc2
  • InChI=1S/C19H20ClNO4/c1-19(2,18(23)24)25-16-9-3-13(4-10-16)11-12-21-17(22)14-5-7-15(20)8-6-14/h3-10H,11-12H2,1-2H3,(H,21,22)(H,23,24) Yes check.svgY
  • Key:IIBYAHWJQTYFKB-UHFFFAOYSA-N Yes check.svgY
   (verify)

Bezafibrate (marketed as Bezalip and various other brand names) is a fibrate drug used as a lipid-lowering agent to treat hyperlipidaemia. It helps to lower LDL cholesterol and triglyceride in the blood, and increase HDL.

Contents

It was patented in 1971 and approved for medical use in 1978. [1]

Medical uses

Bezafibrate improves markers of combined hyperlipidemia, effectively reducing LDL and triglycerides and improving HDL levels. [2] The main effect on cardiovascular morbidity is in patients with the metabolic syndrome, the features of which are attenuated by bezafibrate. [3] Studies show that in patients with impaired glucose tolerance, bezafibrate may delay progress to diabetes, [4] and in those with insulin resistance it slowed progress in the HOMA severity marker. [5] In addition, a prospective observational study of dyslipidemic patients with diabetes or hyperglycemia showed that bezafibrate significantly reduces haemoglobin A1c (HbA1c) concentration as a function of baseline HbA1c levels, regardless of concurrent use of antidiabetic drugs. [6]

Side-effects

The main toxicity is hepatic (abnormal liver enzymes); myopathy and on rare occasions rhabdomyolysis have been reported.

Other uses

The Australian biotech company Giaconda combines bezafibrate with chenodeoxycholic acid in an anti-hepatitis C drug combination called Hepaconda.

Bezafibrate has been shown to reduce tau protein hyperphosphorylation and other signs of tauopathy in transgenic mice having human tau mutation. [7]

The combination of a cholesterol-lowering drug, bezafibrate, and a contraceptive steroid, medroxyprogesterone acetate, could be an effective, non-toxic treatment for a range of cancers, researchers at the University of Birmingham have found. [8]

Mode of action

Like the other fibrates, bezafibrate is an agonist of PPARα; some studies suggest it may have some activity on PPARγ and PPARδ as well. [9]

Synthesis

Further evidence that substantial bulk tolerance is available in the para position is given by the lipid lowering agent bezafibrate.

Bezafibrate synthesis: Bezafibrate synthesis.svg
Bezafibrate synthesis:

The p-chlorobenzamide of tyramine undergoes a Williamson ether synthesis with ethyl 2-bromo-2-methylpropionate to complete the synthesis. The ester group is hydrolyzed in the alkaline reaction medium.

History

Bezafibrate was first introduced by Boehringer Mannheim in 1977.

Related Research Articles

<span class="mw-page-title-main">Coronary artery disease</span> Reduction of blood flow to the heart

Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. CAD can cause stable angina, unstable angina, myocardial ischemia, and myocardial infarction.

<span class="mw-page-title-main">Fat</span> Esters of fatty acid or triglycerides

In nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such compounds, most commonly those that occur in living beings or in food.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle. HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL has been associated with the progression of atherosclerosis.

<span class="mw-page-title-main">Atherosclerosis</span> Inflammatory disease involving buildup of lesions in the walls of arteries

Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and driven by elevated levels of cholesterol in the blood. These lesions may lead to narrowing of the arterial walls due to buildup of atheromatous plaques. At the onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. In severe cases, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney disorders, depending on which body part(s) the affected arteries are located in the body.

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins, such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

<span class="mw-page-title-main">Fibrate</span> Class of chemical compounds

In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid. They are used for a range of metabolic disorders, mainly hypercholesterolemia, and are therefore hypolipidemic agents.

<span class="mw-page-title-main">Hypercholesterolemia</span> High levels of cholesterol in the blood

Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, hyperlipoproteinemia, and dyslipidemia.

Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases, which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for cardiovascular disease, abnormal levels do not mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Simvastatin</span> Lipid-lowering medication

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Hypertriglyceridemia</span> High triglyceride blood levels

Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and high triglyceride levels are associated with atherosclerosis, even in the absence of hypercholesterolemia and predispose to cardiovascular disease.

<span class="mw-page-title-main">Combined hyperlipidemia</span> Medical condition

Combined hyperlipidemia is a commonly occurring form of hypercholesterolemia characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL. On lipoprotein electrophoresis it shows as a hyperlipoproteinemia type IIB. It is the most commonly inherited lipid disorder, occurring in around one in 200 persons. In fact, almost one in five individuals who develop coronary heart disease before the age of 60 have this disorder.

<span class="mw-page-title-main">Gemfibrozil</span> Medication

Gemfibrozil, sold under the brand name Lopid among others, is a medication used to treat abnormal blood lipid levels. It is generally less preferred than statins. Use is recommended together with dietary changes and exercise. It is unclear if it changes the risk of heart disease. It is taken by mouth.

Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Fenofibrate</span> Drug of the fibrate class, mainly used to reduce cholesterol levels

Fenofibrate, is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared to statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol. Its use is recommended together with dietary changes.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

<span class="mw-page-title-main">Cholesterol 7 alpha-hydroxylase</span> Protein-coding gene in the species Homo sapiens

Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.

<span class="mw-page-title-main">APOA5</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

The chronic endothelial injury hypothesis is one of two major mechanisms postulated to explain the underlying cause of atherosclerosis and coronary heart disease (CHD), the other being the lipid hypothesis. Although an ongoing debate involving connection between dietary lipids and CHD sometimes portrays the two hypotheses as being opposed, they are in no way mutually exclusive. Moreover, since the discovery of the role of LDL cholesterol (LDL-C) in the pathogenesis of atherosclerosis, the two hypotheses have become tightly linked by a number of molecular and cellular processes.

References

  1. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 474. ISBN   9783527607495.
  2. Behar S, et al. (Bezafibrate Infarction Prevention (BIP) study) (July 2000). "Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease". Circulation. 102 (1): 21–27. doi: 10.1161/01.cir.102.1.21 . PMID   10880410.
  3. Tenenbaum A, Motro M, Fisman EZ, Tanne D, Boyko V, Behar S (May 2005). "Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome". Archives of Internal Medicine. 165 (10): 1154–1160. doi: 10.1001/archinte.165.10.1154 . PMID   15911729.
  4. Tenenbaum A, Motro M, Fisman EZ, Schwammenthal E, Adler Y, Goldenberg I, et al. (May 2004). "Peroxisome proliferator-activated receptor ligand bezafibrate for prevention of type 2 diabetes mellitus in patients with coronary artery disease". Circulation. 109 (18): 2197–2202. doi: 10.1161/01.CIR.0000126824.12785.B6 . PMID   15123532.
  5. Tenenbaum A, Fisman EZ, Boyko V, Benderly M, Tanne D, Haim M, et al. (April 2006). "Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate". Archives of Internal Medicine. 166 (7): 737–741. doi: 10.1001/archinte.166.7.737 . PMID   16606809.
  6. Teramoto T, Shirai K, Daida H, Yamada N (March 2012). "Effects of bezafibrate on lipid and glucose metabolism in dyslipidemic patients with diabetes: the J-BENEFIT study". Cardiovascular Diabetology. 11 (1): 29. doi: 10.1186/1475-2840-11-29 . PMC   3342914 . PMID   22439599.
  7. Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, Starkova N, et al. (December 2012). "Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice". Human Molecular Genetics. 21 (23): 5091–5105. doi:10.1093/hmg/dds355. PMC   3490516 . PMID   22922230.
  8. "Contraceptive, Cholesterol - lowering drugs used to treat cancer". Science daily. 14 May 2015.
  9. Helmstädter, Moritz; Schierle, Simone; Isigkeit, Laura; Proschak, Ewgenij; Marschner, Julian Aurelio; Merk, Daniel (2022-09-03). "Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists". International Journal of Molecular Sciences. 23 (17). doi: 10.3390/ijm . PMC   9456086 . PMID   36077469. Archived from the original on 2024-12-16.
  10. DE 2149070,Witte EC, Stach K, Stork H, Thiel M, Schmidt F,"Phenoxyalkylcarbonsäurederivate und Verfahren zur Herstellung derselben [Phenoxyalkylcarboxylic acid derivatives and processes for the production of the same]",published 1973-04-05,issued 23 April 1978, assigned to Boehringer Mannheim GmbH
  11. US 3781328,Witte EC, Stach K, Stork H, Thiel M, Schmidt F,"Phenoxy-alkyl-carboxylic acid compounds",issued 25 December 1973, assigned to Boehringer Mannheim GmbH