Cholesterol ester transfer protein inhibitors

Under the same conditions, tricyclo[5.3.1.0]undecanes are accessible from 5-sub-stituted 2-cyclohexen-l-one as 2-370 with a shorter tether by one CH2-group. Recently, another Michael/Michael/aldol transformation was employed by Paulsen and coworkers to obtain access to the central aromatic core of compounds as 2-376 (Scheme 2.89) [206]. It is of value that such products are thought to act as cholesterol ester transfer protein (CETP) inhibitors, and the application of these drugs should prevent reduction of the HDL-cholesterol level and therefore reduce the risk of coronary heart diseases [207]. 

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). ... 

Kelkar, M.A., Pednekar, D.V., Pimple, S.R. and Akamanchi, K.G. (2004) 3D QSAR studies of inhibitors of cholesterol ester transfer protein (CETP) by CoMFA. CoMSlA and GFA methodologies. Med. Chem. Res., 13, 590-604. 

Cholesterol ester transfer protein (CETP) inhibitors Gumkowski et al. (2005)... 

This experience is worth revisiting. Does it suggest that such large effects on HDL cholesterol cannot overcome the adverse effects of a modest increase in blood pressure Does that itself cast some doubt on the HDL hypothesis, or will other inhibitors of cholesterol ester transfer protein (CETP) reveal problems not associated with blood pressure Several major companies are advanced in their trials of CETP inhibitors. One, anacetrapib, has been found to be free of the mineralocorticoid-related blood pressure effects and is equi-potent with torcetrapib and another compound already in a large outcome trial. These inhibitors bind CETP to HDL and there are differences between the compounds to the extent of the reversibility of the binding [SEDA-32, 816]. 

Massa MA, Spangler DP, Durley RC, Hickory BS, CotmoUy DT, Witherbee BJ, Smith ME, Srkorski JA (2001) Novel heteroaryl replacements of aromatic 3-tetrafluoroethoxy substituents in trifluoro-3-(tertiaiyamino)-2-propanols as potent inhibitors of cholesterol ester transfer protein. Bioorg Med Chem Lett 11 1625-1628... 

Brousseau ME, Schaefer EJ, Wolfe ML,etal. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004 350 1505-15. 

Cholesterol lowering drugs are indicated for the prevention and treatment of atherosclerosis. There are three families of these dmgs inhibitors of HMG-CoA reductase (statins), inhibitors of cholesterol transport protein, and inhibitors of cholesteryl ester transfer protein (CETP). They are important drugs from an economical point of view. Among them, several are fluorinated. 

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