ChemicalBook > Product Catalog > API > Circulatory system drugs > Lipid regulating drugs > Clofibrate
- Product Name:Clofibrate
- Synonyms: alpha-(p-chlorophenoxy)-isobutyricaciethylester alpha-p-Chlorophenoxyisobutyryl ethyl ester alpha-p-chlorophenoxyisobutyrylethylester Amotril Amotril S amotrils Angiokapsul Anparton
- Product Categories: - Aromatics Compounds Aromatics Intermediates & Fine Chemicals Pharmaceuticals Intracellular receptor NIMOTOP
- Mol File:637-07-0.mol
Clofibrate Chemical Properties
- Boiling point:154 °C
- Density 1.14 g/mL at 25 °C(lit.)
- refractive index n
- Flash point:113 °C
- storage temp. 2-8°C
- solubility Soluble to 100 mM in DMSO.
- form liquid
- color clear, colorless
- Merck 14,2377
- BRN 1913459
- CAS DataBase Reference637-07-0(CAS DataBase Reference)
- NIST Chemistry ReferenceClofibrate(637-07-0)
- EPA Substance Registry SystemPropanoic acid, 2-(4-chlorophenoxy)-2-methyl-, ethyl ester(637-07-0)
- Hazard Codes Xn,N
- Risk Statements 22-37/38-41-51/53-40
- Safety Statements 26-36/37/39-61-45-36/37
- RIDADR UN 3082 9/PG 3
- WGK Germany 3
- RTECS UE9480000
- HazardClass 9
- HS Code 29189900
- Hazardous Substances Data637-07-0(Hazardous Substances Data)
- ToxicityLD50 in mice, rats (g/kg): 1.28, 1.65 orally (Metz)
Clofibrate Usage And Synthesis
- Chemical PropertiesClear Colorless Oil
- Usesinhibits cholesterol biosynthesis
- DefinitionChEBI: The ethyl ester of clofibric acid.
- brand nameAtromid (Wyeth);Aatroayerst;Aitiflus;Angiocapsul;Arterioflexion;Artriosan;Asa/cpib;Aterioplexin;Ateroayrest;Ateroclar;Aterofront;Ateronlen;Aterosol;Atevil;Atheroayerst;Atrofort;Atrolan;Atromid-s;Atrom-s;Ay 61;Biocleran;Clareden;Cloberab;Clobrate;Clobren-5 f;Clofenit;Clofibral;Clofibrate ayerst;Clofibrate compose;Clofibrato ayerst;Clofibrato procaps;Clofibrem;Clofimide;Clofin-icn;Clofipront 5000;Clofirem;Clofirin;Clofi-t;Clopin;Col 180;Contra-lipide;Corafen;Cr/085;Dabical;Dilectus;Doctus;Duplinal;Duraclofibrate;Ellemger;Eramid;Fibramid;Fibrolynt;Geri-70;Geromid;Healthstyle;Ici 28257nt;Ipolipid;Kontalipide;Levatram;Liapten;Liparil;Lipaten;Lipavlon 500;Lipicidon;Lipidicon;Liporan;Liptrinal;Lostat;Neoatromid;Nibratal;Nibratol;Nnormet;Nobret;Norinolipol;Normet richter;Nosterolin;Novofibrate;Omelip;Provasa;Recade;Regelan n 500;Sclerovasal;Serolipid;Sinteroid;Sklerocip;Sklerolip;Sklerovasal;Supraoxid;Tepincal;Tepingal;Vimedel;Vocaline.
- World Health Organization (WHO)Clofibrate, an antihyperlipidaemic agent, was introduced in 1967 and was subsequently extensively studied in the primary and secondary prevention of ischaemic heart disease. Following reports, published in 1978, of increased mortality among patients receiving clofibrate in a WHO-sponsored cooperative trial concerned with the primary prevention of ischaemic heart disease, the drug was withdrawn in some countries and its approved indications were severely restricted in many others. These restrictions have become the norm for more recently developed analogues of clofibrate. (Reference: (WHODI) WHO Drug Information, 2, 6, 1979)
- General DescriptionClofibrate, ethyl 2-(p-chlorophenoxy)-2-methylpropionate (Atromid-S), is a stable, colorless topale yellow liquid with a faint odor and a characteristictaste. It is soluble in organic solvents but insoluble in water.
Clofibrate is prepared by a Williamson synthesis, condensingp-chlorophenol with ethyl -bromoisobutyrate, or bythe interaction of a mixture of acetone, p-chlorophenol, andchloroform in the presence of excess potassium hydroxide.The acid obtained by either of these methods is esterified togive clofibrate. Both acid and ester are active; the latter, however,is preferred for medicinal use. Clofibrate is hydrolyzedrapidly to 2-p-chlorophenoxy-2-methylpropionic acid by esterasesin vivo and, bound to serum albumin, circulates inblood. The acid has been investigated as a hypolipidemicagent. It is absorbed more slowly and to a smaller extent thanis the ester. The aluminum salt of the acid gives even lowerblood levels than p-chlorophenoxy-2-methylpropionic acid.
- HazardQuestionable carcinogen; toxic; causes nausea, vomiting, diarrhea, weakness, stiffness, cramps, and muscle tenderness.
- Biological ActivityPPAR agonist (EC 50 values are 50, 500 and > 100 μ M at PPAR α , PPAR γ and PPAR δ respectively). Antihyperlipoproteinemic.
- Mechanism of actionThe three structurally related fibrates available in the
United States are gemfibrozil (Lopid), fenofibrate
(Tricor) and clofibrate (Atromid-S).They share common
uses and toxicities. The fibrates typically lower VLDL
triglyceride by 40% or more and elevate plasma HDL
cholesterol by 10 to 15%. The reduction of plasma
triglycerides in humans appears due to increased lipoprotein
lipase (LPL) activity. The fibrates activate a nuclear
receptor (transcription factor) termed peroxisomal proliferation
activated receptor (PPAR) that is a member of
the steroid hormone receptor superfamily. PPAR increases
transcription of the LPL gene and decreases transcription
of the apolipoprotein CIII gene (apo CIII).
Since LPL is responsible for catabolism of VLDL triglyceride
and apo CIII is an inhibitor of LPL activity, the
combined consequences of these changes are increased
LPL activity and enhanced removal of triglyceride from
The elevation of HDL levels by fibrates may be due to two drug actions: induced synthesis of apo-A1, the principal apoprotein of HDL, and increased assembly of new HDL particles in the circulation. Surface components of VLDL contribute to formation of HDL, as the VLDL particles are reduced in size through the action of LPL.The increased rate of catabolism of VLDL caused by the fibrates would provide more components for assembly of HDL particles.
- Clinical UseClofibrate is the drug of choice in the treatment of typeIII hyperlipoproteinemias and may also be useful, to a lesserextent, in types IIb and IV hyperlipoproteinemias. The drugis not effective in types I and IIa.
Clofibrate can lower plasma concentrations of both triglyceridesand cholesterol, but it has a more consistent clinicaleffect on triglycerides. It also affects lipoprotein plasmalevels by enhancing removal of triglycerides from the circulationand causes reduction of VLDL by stimulatinglipoprotein lipase to increase the catabolism of this lipoproteinto LDL. Clofibrate lowers triglyceride levels in theserum much more than cholesterol levels and decreases levelsof FFAs and phospholipids. The lowering of cholesterollevels may result from more than one mechanism. Clofibrateinhibits the incorporation of acetate into the synthesis ofcholesterol, between the acetate and mevalonate step, by inhibitingsn-glyceryl-3-phosphate acyltransferase. Clofibratealso regulates cholesterol synthesis in the liver by inhibitingmicrosomal reduction of 3-hydroxy-3-methylglutaryl-CoA(HMG-CoA), catalyzed by HMG-CoA reductase. Clofibratemay lower plasma lipids by means other than impairment ofcholesterol biosynthesis, such as increasing excretionthrough the biliary tract.
- Side effectsThe fibrates are generally well tolerated, with GI distress being the most likely complaint. Other adverse effects include myositis and erectile dysfunction, particularly with clofibrate. There is ongoing concern about the fibrates increasing the risk of gallstones, although the extent of risk is unclear. Because clofibrate was associated with increased mortality in early clinical trials, it should be considered as a second-line drug.
- Drug interactionsThe fibrates potentiate the actions of the coumarin anticoagulants, such as warfarin, so care should be taken to reduce the dose of simultaneously administered anticoagulants, and plasma prothrombin should be frequently measured until the level stabilizes. As mentioned earlier, great care should be given to combining a statin with a fibrate, since this combination may increase the risk of myositis and perhaps rhabdomyolysis.
Clofibrate Preparation Products And Raw materials
- Ethyl propiolate Beclobrate Ethyl cyanoacetate Etanol Ethylparaben 2-(4-Chlorophenoxy)-2-methylpropionic acid Butyl acetate 4-Chloronitrobenzene Ethyl acetate p-Dichlorobenzene Ethyl acrylate Phenoxyethyl isobutyrate Butyl acrylate Chlorpheniramine maleate Ethyl butyrate Tributyl phosphate Ethyl 2-methylbutyrate DL-Ethyl 2-bromobutyrate
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