The common mode of action of three new classes of inhibitors of cholesterol biosynthesis

Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat.

“…1 -5 In laboratory animals such as the rat, fibrates are extremely effective in lowering plasma cholesterol and' occasionally plasma triglyceride concentrations. 6 - 11 Although very little is known about the exact mechanism of action of these drugs, the decreases in plasma cholesterol and triglyceride levels are classically thought to be the result of a decrease in hepatic cholesterol synthesis 712 -14 and the induction of lipoprotein lipase in peripheral tissues, 15 -20 respectively. In addition, fibrates have been shown to be potent inducers of the /3-oxidation system of fatty acids in the liver and, to a lesser extent, in the intestine and kidney in rodents.…”

Structure/Activity Relationship of Gemfibrozil (CI-719) and Related Compounds

“…Among disubstituted derivatives, activity patterns indicated that 2,5and 3,5-substitution produced a maximum response where both substituents were methoxy or chloro (not shown) as well as the dimethyl analogues shown in Table 3. The dimethyl substituted congeners shown, displayed greatest activity (Creger 1972a 0 Acacia suspensions of the drugs were administered daily by gavage to groups of 10 male rats for seven days (Rodney et al 1965) analogues (not shown) were significantly less active, and mixed methyl-alkyl and methylchloro derivatives (not shown) likewise displayed lower effects than (30) (33) or (4). Earlier work in another series of compounds indicated that ester or carboxyl functions are not necessary for activity in antihyperlipidemic agents (Creger 1966).…”

“…This method was used, therefore, to prepare the two series of analogues shown in Table 1. The Table 1 Effect of chain spacing on plasma lipids X\ COH Percentage reduction in plasma lipids Dosec * Acacia suspensions of the drugs were administered daily by gavage to groups of 10 male rats for seven days (Rodney et al 1965) structures correspond to (II) where G is phenyl or phenoxy and Cn is an aliphatic chain. These models were examined initially to assess the effect of chain spacing on lipid levels in normal rats (VanHandel & Zilversmit 1957).…”

“…These models were examined initially to assess the effect of chain spacing on lipid levels in normal rats (VanHandel & Zilversmit 1957). When the drugs were administered by gavage (Rodney et al 1965), good activity was displayed in compounds 4-8 when the phenoxy and isobutyric acid fragments were spaced by three or more carbon atoms (Creger 1972b). Moderate activity was obtained for analogues 12-14 in which the ether oxygen atom was replaced by a methylene group.…”

“…Acacia suspensions of the drugs were administered daily by gavage to groups of 10 male rats for seven days(Rodney et al 1965) …”