CETP inhibition

A recently developed antihyperlipidemic is ezetimibe (Zetia, A.113) (Figure A.31). Ezetimibe inhibits the absorption of cholesterol across the intestinal wall. Like fibrates, ezetimibe is often prescribed with statins, although the effectiveness of ezetimibe has recently been called into question. A compound that may soon be approved for the treatment of high cholesterol is anacetrapib (A.114). Anacetrapib, a product of Merck, is currently in phase III trials. The compound inhibits cholesteryl ester transfer protein (CETP). The net effect of CETP inhibition is elevated HDL cholesterol and lower LDL cholesterol levels. 

Since sclerotiorin, a member of the azaphilone family, was found to inhibit CETP activity, the effect of azaphilones on CETP activity was tested. A structure-specific CETP inhibition by azaphilones was shown. Electrophilic ketone(s) and/or enone(s) at both the C-6 and C-8 positions of the isochromane-like ring are neces-... 

Figure 6 Consensus structure of azaphilones for CETP inhibition (A) and hypothetical mechanism of reaction of sclerotiorin with e-amino residue of lysine (B).

CETP is a hydrophobic plasma glycoprotein, mainly synthesized in the liver, that possesses the unique ability to facilitate the transfer of cholesteryl ester (CE). CETP circulates in the blood, bound predominantly to HDL. CETP mediates the transfer of cholesteryl esters from HDL to VLDL and LDL in exchange for triglycerides. CETP also promotes the transformation of HDL2 to HDL3, an action that could promote reverse cholesterol transport. CETP inhibition produces an increase in HDL by markedly delaying the catabolism of apoA-I and A-II (129), an action that increases reverse cholesterol transport. These actions of CETP suggest that CETP inhibition could prevent atherosclerosis (130-132). 

The plasma of several animal species has been found to contain a protein that can inhibit the CETP-mediated exchange of both CE and TG [79]. The presence of this protein may account for the apparent lack of CETP activity in some species. In particular, the plasma of animals such as the rat appears to contain a large amount of the inhibitor, which has an apparent molecular weight of 35 000 and a p7 of <4 [79]. Addition of plasma from rat or pig, both of which exhibit little detectable CETP activity, to partially purified rabbit CETP inhibited its activity [79]. 

The recent years have seen the success of statins like Lipitor (atorvastatin) as hypolipidemic agents that help treating cardiovascular disease primarily by lowering low-density lipoproteins ( bad cholesterol ) levels. Another novel strategy is to tackle the same problem by elevating high-density lipoproteins (H D L or good cholesterol ) levels via inhibition of cholesteryl ester transfer protein (CETP). 

Choiesteryi Ester Transfer Protein inhibitors Cholesterol ester transfer protein (CETP) is a glycoprotein that transfers choiesteryi ester from HDL (high density lipoprotein) to proatherogenic apolipoproteins (LDL—(low density lipoprotein). Its inhibition has beneficial effects at the level of HDL cholesterol. SC-71952 and torcetrapib are highly fluorinated CETP inhibitors. SC-71952 is a disymmetrical sulfide with 10 fluorine atoms. Torcetrapib contains three CF3 groups (Figure 8.61). ... 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

The compound 19 also inhibited the activity of cholesteryl ester transfer protein (CETP) with an IC50 value of 98 pM. The compounds 18, 20 and 21 weakly inhibited the activity of CETP in 300 pM. 

Mice and other animal models of disease are often poor mimics of the human condition. However, the expression of human genes in these animals can initiate development of the disease. In mice, the distribution of cholesterol between low-density lipoproteins (LDL) and high-density lipoproteins (HDL) is quite distinct from that in humans. However, if the human enzyme, cholesterol ester transfer protein (CETP) is expressed in mice, the ratio of LDL HDL becomes more human in profile. Inhibition of CETP is a target for antiatherosclerotic drags and there now exists an animal model in which to test them. 

C22H32O3, Mr 344.48, amorphous solids. Merosesqui-terpenes from the sponge Xestospongia wiedenmayeri. W. inhibit cholesterylester-transferprotein (CETP), having anti-atherosclerotic potential, see avarol. 

In summary, the introduction of CETP into mice that usually do not carry this gene markedly reduces HDL levels. It also facilitates the accumulation of cholesterol in flie liver, and subsequently inhibits the expressions of proteins involved in... 

Decreased Apo A1 appears to be a major component of the dyslipi-demic serum profile in patients with atherosclerotic occlusive disease of the lower extremities (461). Despite similar TC and HDL-C levels, A1 HDL is more anti-atherogenic than A1/A2 HDL in transgenic mice (462). This is because lecithinxholesterol acyltransferase (LCAT) and cholesteryl ester trasfer protein (CETP) are present mainly in Lp A1 and because Lp A1 A2 can inhibit Lp A1 -promoted cholesterol efflux. Also, mice overexpressing Apo A1 have more cholesterol efflux and are more protected against atherosclerosis mediated through decreased foam cell... 

Apo AH alters reverse cholesterol transport, but also may inhibit LCAT activity (deleterious effect), CETP activity (beneficial effect), may increase hepatic lipase activity (beneficial effect), and may inhibit the hepatic cholesteryl uptake from HDL (deleterious effect) (reviewed in ref. 472). There is a positive association of Apo AH with FFA and... 

As mentioned earlier, decreased HDL-C levels constitute a major risk factor for CAD and LEAD. A novel therapeutic approach to raise HDL is inhibition of cholesteryl ester transfer protein (CETP) (123). Individuals with CETP deficiency as a result of molecular defects in the CETP gene, have markedly elevated plasma levels of HDL-C and apoli-poprotein A-I (124). 

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