Cholesteryl ester transfer protein (CETP), a plasma glycoprotein, mediates the transfer of neutral lipids in the blood among various lipoproteins.1,2 Because of their poor water solubility, neutral lipids such as triglycerides (TG), free cholesterol (FC), and cholesteryl esters (CE) generally are not freely circulating in plasma but instead are packaged together and transported through the body in larger lipoprotein particles that have amphipathic lipids and proteins as surface components. Low-density lipoprotein (LDL) and high-density lipoproteins (HDL) particles help move cholesterol to and from the periphery, respectively. The entire transport process is highly regulated in terms of lipoprotein production and the transfer of lipids to and from these particles. CETP facilitates the transfer of CE from HDL containing apolipoprotein-A (apo-A) to apo-B-containing lipoproteins such as very-low-density lipoprotein (VLDL) and LDL with a balanced exchange of TG. For every CE acquired from HDL and transferred to LDL or VLDL, CETP takes up one TG molecule from LDL or VLDL and transfers it to HDL. Thus, CETP plays a critical role in both CE and TG transfer among lipoproteins. A CETP inhibitor would thus be expected to raise plasma HDL cholesterol (HDLc) levels, lower LDL cholesterol (LDLc), and provide a potential therapeutic benefit for patients with coronary artery disease (CAD). As discussed in more detail below, whether CETP inhibition might induce an antiatherogenic response by raising HDLc or have proatherogenic effects by interfering with reverse cholesterol transport (RCT) has been the subject of considerable debate and controversy.2-5 Important insights from studies over the past several years have added to our understanding of the multiple mechanisms by which HDL achieves its atheroprotective effects6 and the complex physiological and pathophysiological roles CETP plays in lipoprotein metabolism. However, the field still remains controversial. Recently, a number of potent, selective, and orally active CETP inhibitors have also been identified that raise HDLc in animals and more clearly define the role of CETP in preclinical models of atherosclerosis.2 Several of these new CETP inhibitors have been brought forward and evaluated in clinical trials, and two have now independently demonstrated phase II proof of concept by dramatically increasing HDLc levels by 50% or more in healthy volunteers and patients with low HDLc.7,8 Thus, for the first time, pharmacological agents are available that have the potential to elevate HDLc in patients with low HDLc to about the same extent that the current standard of care drugs reduce LDLc in hyperlipidemic patients. These exciting clinical results have generated renewed interest in CETP inhibition as a potential new therapeutic strategy for treating CAD, and more than 750 related patents or publications have appeared in Chemical Abstracts since 2000. It remains to be seen whether prolonged treatment with these new agents leads to a profound reduction in secondary coronary events across a broader patient population without disrupting normal lipoprotein balance and function. This Perspective summarizes the current status of orally active CETP inhibitors as potential new treatments for CAD.

Oral cholesteryl ester transfer protein (CETP) inhibitors: a potential new approach for treating coronary artery disease.

The enantioselective enamine/trifluoropyruvate condensation features the synthesis of a series of fused pyrrole derivatives such as (III), (IX), (XI), or (XIII).

Cinchona Alkaloid/TiIV-Catalyzed Enantioselective Enamine–Trifluoropyruvate Condensation–Cyclization Reaction and Its Application to Drug-like Heterocycles

2-(4-carbonylphenyl)benzoxazole inhibitors of CETP: scaffold design and advancement in HDLc-raising efficacy.

Novel tetrahydrochinoline derived CETP inhibitors.

The invention relates to novel tetrahydroquinoline derivatives of formula (I), wherein R1 represents cyclohexyl or cyclopentyl, R2 and R3 each represent methyl or jointly form a cyclobutane, and R4 represents cyclopentyl or isopropyl, the salts and solvates thereof, and the solvates of said salts. Also disclosed are a method for the production thereof, the use thereof on its own or in combinations for the treatment and/or prevention of diseases, and the use thereof for producing medicaments, particularly as a cholesterol ester transfer protein (CETP) inhibitor in order to treat and/or prevent cardiovascular diseases, especially hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia, and arteriosclerosis.

(5s) -3-[(s)-fluoro (4-trifluoromethylphenyl) methyl]-5,6,7,8-tetrahydroquinoline-5-ol derivatives and use thereof as cetp inhibitors

The inhibition of the cholesteryl ester transfer protein (CETP) provides a method for the elevation of the high density lipoprotein cholesterol (HDL-C) level, i.e. the 'good' cholesterol. The expected anti-atherogenic effect of this approach is independent of the proven benefits of lowering the low density lipoprotein cholesterol (LDL-C) level, i.e. the 'bad' cholesterol. A medicinal chemistry project is presented starting from the first screening hit to the second generation development candidate. The structure-activity relationship, the syntheses and the role of fluorine during optimization, as well as the biological activities are discussed.

Holger Paulsena

Papers

Fluorine-substitution in cholesteryl ester transfer protein inhibitors (CETP-inhibitors): Biology, chemistry, SAR, and properties