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Bezafibrate

Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a682711
Routes of administration	Oral
ATC code	C10AB02 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Identifiers
IUPAC name 2-(4-{2-ethyl}phenoxy)-2-methylpropanoic acid
CAS Number	41859-67-0
PubChem CID	39042
IUPHAR/BPS	2668
DrugBank	DB01393
ChemSpider	35728
UNII	Y9449Q51XH
KEGG	D01366
ChEBI	CHEBI:47612
ChEMBL	ChEMBL264374
CompTox Dashboard (EPA)	DTXSID3029869
ECHA InfoCard	100.050.498
Chemical and physical data
Formula	C19H20ClNO4
Molar mass	361.82 g·mol
3D model (JSmol)	Interactive image
SMILES O=C(c1ccc(Cl)cc1)NCCc2ccc(OC(C(=O)O)(C)C)cc2
InChI 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) Key:IIBYAHWJQTYFKB-UHFFFAOYSA-N
(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.

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

Medical uses

Bezafibrate improves markers of combined hyperlipidemia, effectively reducing LDL and triglycerides and improving HDL levels. The main effect on cardiovascular morbidity is in patients with the metabolic syndrome, the features of which are attenuated by bezafibrate. Studies show that in patients with impaired glucose tolerance, bezafibrate may delay progress to diabetes, and in those with insulin resistance it slowed progress in the HOMA severity marker. 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.

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.

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.

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.

Synthesis

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

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.

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. DE 2149070, Witte EC, Stach K, Stork H, Thiel M, Schmidt F, "Phenoxyalkylcarbonsäurederivate und Verfahren zur Herstellung derselben ", published 1973-04-05, issued 23 April 1978, assigned to Boehringer Mannheim GmbH 
10. 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 

• 2-Methyl-2-phenoxypropanoic acid derivatives
• 4-Chlorophenyl compounds
• Benzamides