Phenoxyisobutyric acids

Fibrates can be chemically classified as analogues of phenoxyisobutyric acid. Literature references to the SARs for this class of drugs are sparse however, all compounds are analogues of the following general structure. 

In awareness of the lipid-lowering effect of oestrogen observed in the 1960s, ICI conducted a targeted search for substances, which possess no oestrogenic but lipid-lowering properties. They struck it lucky with compounds related to 2-phenoxyisobutyric acid (red). In 1968, clofibrate came to the market. There followed a series of other drugs with similar structures and the same mode of action. 

A Rapid Gas Chromatographic Method for the Determination of Chloro-phenoxyisobutyric Acid in Plasma and Urine... 

A High Pressure Liquid Chromatographic Determination of p-Chloro-phenoxyisobutyric Acid and Its Comparison to a GLC and an Ultraviolet Spectrophotometric Method Clin. Biochem. (ooawa) 11(5) 214-217 (1978) CA 90 33693q... 

A semi-polar cyclic five-membered transition state has been proposed to account for the unimolecular pyrolysis kinetics of primary, secondary, and tertiary 2-phenoxycarboxylic acids in the gas phase reaction rates increase in the order 2-phenoxyacetic, 2-phenoxypropionic, 2-phenoxybutyric, and 2-phenoxyisobutyric acid. Phenol formation in the rate-determining step is followed by formation and subsequent decompositon of an intermediate lactone to give carbon monoxide and the corresponding carbonyl compound however, in the case of 2-phenoxyisobutyric acid, a parallel elimination reaction gives phenol and methacrylic acid." ... 

Figure 1. The chemical structure of LR-90, methylene bis [4,4 -(2 chlorophenylureido phenoxyisobutyric acid)]...

The laboratory must be informed when the therapeutic regimens include drugs specifically administered to change the blood level of a biochemical constituent. Cholestyramine resin, a nonabsorbable anion exchange resin administered orally to patients with hyperlipoproteinemia produced a 24% decline in serum cholesterol levels in 14 patients with essential hypercholesterolemia. In these patients the mean cholesterol fell from 414 98 mg/100 ml to 176 21 mg/100 ml (FI). Pectin added to the diet caused a 5% decrease in serum cholesterol values (K4), as did an oral hydrophobic colloid (G4). Levels fell in one case from 220 mg/ 100 ml to 160 mg/100 ml (G4). Nicotinic acid, neomycin, and p-chloro-phenoxyisobutyrate have all been used to reduce serum cholesterol (G7). 

Besides their action on cholesterol biosynthesis, nicotinic acid and chloro-phenoxyisobutyrate (CPIB) could also interfere with cholesterol degradation. In fact, nicotinic acid enhances cholesterol side-chain oxidation by rat-liver mitochondria, an action shared by 3-pyridylacetic acid which has also been reported to have hypocholesterolaemic properties. 

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