Ethyl-p-chlorophenoxyisobutyrate

Experiments with various alpha-hydroxyisobutyric acid derivatives led to the finding of the striking effect on serum lipids produced by ethyl-p-chlorophenoxy-isobutyrate (CPIB). Initially, the material was used in combination with an-drosterone as Atromid until it was shown by several authors (Hellman et al. 1963, and others) that the active ingredient was actually CPIB alone. Early reports were given by Hellman et al. (1962) as in many other studies concerned with the evaluation of hypocholesterolemic effects, the patients were not selected for symptomatic and idiopathic hypercholesterolemias, and only the plasma cholesterol levels were used as reference points. 

Berkowitz (1963) found lowering of serum cholesterol in 75% of his 25 hyperlipidemic patients. Counihan and Keelan (1963) reported even better results with lowering of serum cholesterol in 16 out of 17 hypercholesterolemic patients, whereas in a person with normal cholesterol level the opposite reaction was observed. Green et al. (1963) found in 601 patients, 

2 Imperial Chemical Industries Ltd., Alderley Park, Cheshire, England. 

Comparative studies in patients with EFH and essential hyperlipemia, on the effect of CPIB and dextrothyroxine on low and very low density lipoproteins respectively, were performed by Strisower and Strisower (1964). CPIB lowered very low density lipoproteins (and thus triglycerides) more than dextrothyroxine, but the latter drug was superior to CPIB as regards the depressing effect on serum beta-lipoproteins and thus on cholesterol (see also page 434). 

The mode of action of the drug has not been clarified. Some relevant theories have been discussed in the chapter on essential hyperlipemias. 

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The ethyl p-chlorophenoxyisobutyrate may be obtained by heating a mixture of 206 parts of dry p-chlorophenoxyisobutyric acid, 1,000 parts of ethanol and 40 parts of concentrated sulfuric acid under reflux during 5 hours. The aicohol is then distilled off and the residue is diluted with water and extracted with chioroform. The chloroform extract is washed with sodium hydrogen carbonate solution, dried over sodium sulfate and the chloroform removed by distillation. The residue is distilled under reduced pressure and there is obtained ethyl p-chlorophenoxyisobutyrate, BP 148° to 150°C/20 mm. 

Chemical Name 2-(4-Chlorophenoxy)-2-methylpropanoic acid ethyl ester Common Name Ethyl p-chlorophenoxyisobutyrate Structural Formula ... 

Malhotra, S.C., and M.M. Ahuja. 1971. Comparative hypolipidaemic effectiveness of gum guggulu (Commiphora mukul) fraction A, ethyl-p-chlorophenoxyisobutyrate and Ciba-13437-Su. Indian J. Med. Res. 59(10) 1621-1632. 

Kritchevsky, D., Sallata, R, and Tepper, S.A. (1968) Influence of Ethyl p-Chlorophenoxyisobutyrate (CPIB) upon Establishment and Progression of Experimental Atherosclerosis in Rabbits, J. Atheroscler. Res. 8,755-761. 

Reddy, J. K., and Qureshi, S. A. (1979). Tumorigenicity of the hypolipidaemic peroxisome proliferator ethyl-alpha-p-chlorophenoxyisobutyrate (clofibrate) in rats. Br J Cancer 40, 476-482. 

Clofibrate, the prototype of the fibric-acid derivatives, is the ethyl ester of p-chlorophenoxyisobutyrate. Gemfibrozil is a nonhalogenated phenoxypentanoic acid and thus is distinct from the halo-generated number of fibric-acid analogs (e.g., fenofibrate, bezafibrate, and ciprofibrate have been developed and are used). 

It has recently been reported (1) that administration of the hypolipidemic drug clofibrate (ethyl-a-p-chlorophenoxyisobutyrate) to rats is followed by a great increase of the CoA-pool in their liver. The increase may amount to about 3-fold, and is mainly due to an increase of free CoA (1,2). 

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