CETP inhibition cholesteryl ester transfer protein

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. 

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). 

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. 

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). 

Inhibition of cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL particles and other lipoprotein fractions to atherogenic apo B-containing lipoproteins, leads to a substantial increase in HDL-Cconcentrations and also reduces LDL-C concentrations. Torcetrapib, the first CETP inhibitor evaluated in phase III clinical trials, caused increases in all-cause mortality and cardiovascular events, despite a dramatic increase in HDL-C concentrations. This paradox was explained by stimulation of aldosterone production, leading to increased blood pressure and low serum potassium [23]. Consequently, the large clinical outcomes trial, ILLUMINATE, was prematurely terminated in 2006. 

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