CETP 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]. 

MK-0859 is another CETP inhibitor that has advanced into Phase II clinical trials [79,80]. In addition, a number of novel inhibitors of CETP have emerged from different pharmaceutical companies but their current status is unclear [81-88]. 

Cetane engine, 12 422 Cetane number, 18 668 of diesel fuel, 12A22-A23 Ceteareth-10, cosmetic surfactant, 7 834t Ceteareth-40, cosmetic surfactant, 7 834t Cetoleic acid, physical properties, 5 31t Cetone alpha, 24 565 CETP inhibitors, 5 144t Cetrimonium bromide (CTAB), 4 358t. 

On 2nd December 2006, Pfizer, whose CETP inhibitor torcetrapib (CP-529414) was the first compound aimed at this target, announced that its development had to be stopped in phase III. Of 7500 patients who were given a combination of torcetrapib and atorvastatin, 82 had died, while in the other arm of the study, where patients were given atorvastatin alone, only 51 of 7500 patients had died. There was also a significant rise in blood pressure observed in the group that received torcetrapib. 

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). ... 

Figure 8.61 Choiesteryi ester transfer protein (CETP) inhibitors.

Ex vivo tests for CETP inhibitors were reported using transgenic mice expressing human CETP and human apo A-I [80] or hamsters [81], For example, a test sample dissolved in Cremophor EL solution (4 pi, final 10 mg/kg) is administered to male mice (fasted overnight). Blood is taken at 4 and 24 hr after dosing, and is centrifuged immediately to obtain plasma. The plasma (25 pi) is used as a CETP source to determine the CETP activity by method A. 

Over 20,000 samples of microbial culture broths were subjected to our screening program for CETP inhibitors by method A. At first no BSA was added to the assay mixture, but many false-positive compounds such as fatty acids were isolated. To prevent this, the optimal concentration of BSA was tested and set up as 200 pM, resulting in a low hit rate in the primary screen. The serum albumin concentration in the assay is similar to that in human plasma. Finally, we discovered erabulenols from a fungal strain, and ferroverdins from an actinomycete strain, as novel CETP inhibitors (Fig. 5). 

Figure 5 Structures of CETP inhibitors of natural (A) and synthetic (B) origin.

Data have been presented for the ex vivo and in vivo evaluation of CETP inhibitors. Ex vivo efficacy was shown using hamsters for CGS 25159 (oral administration at 10 mg/kg) [81] and using transgenic mice for sclerotiorin [80] and L681512 (oral administration at 10 mg/kg) [98], Furthermore, analysis of plasma lipoproteins from CGS 25159-treated (10 and 30 mg/kg, p.o.) hypercho-lesterolemic hamsters showed in vivo efficacy with an increase in HDL cholesterol [81],... 

H Shinkai, K Maeda, H Okamoto. Compounds effective as CETP inhibitors. Japanese Patent 11,049,743, 1999. 

Figure 13.2 Effect of inserting a human CETP gene on cholesterol lipoproteins in E3L mice fed a Western-type diet containing 0.25% cholesterol. The E3L.hCETP mouse has shown to respond to statins, fibrates, and the new CETP inhibitor torce-trapib in a similar way as humans do, as manifested by decreased apoB-containing lipoproteins and increased HDL levels.

Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, Hu B, McErlean E, Nissen SE (2011) Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol a randomized controlled trial. JAMA 306 2099-2109... 

Niacin, statins, CETP inhibitors, apoA-l mimetics, and ezetimibe as pharmacological modulators of lipid homeostasis... 

Plasma (PM) lipoprotein profiles play an important role in the development of atherosclerosis, a major cause for cardiovascular mortality. In 1996, Xia et al. disclosed, by random screening and structure-activity relationship (SAR) development, a new class of cholesteryl ester transfer protein (CETP) inhibitors, namely, the 2,4,6-trisubstituted... 

Xie, L., Li, J., and Bourne, P. E. 2009. Drug discovery using chemical systems biology Identification of the protein-ligand binding network to explain the side effects of CETP inhibitors. PLoS Comput. Biol. 5 el000387. 

Zhu and co-workers [77] have successfully developed the first organocatalytic enantioselective three-component Povarov reaction for the efficient synthesis of enantiomerically enriched (2,4-cis)-4-amino-2-aryl(alkyl)-tetrahydroquinolines. To illustrate the power of this novel catalytic enantioselective three-component Povarov reaction, they applied this methodology to the short and efficient synthesis of torcetrapib (188), a potent cholesteryl ester transfer protein (CETP) inhibitor (Scheme 17.31). Reaction of 4-trifluoromethylaniline 184, propionaldehyde 18, and enecarbamate 185 using phosphoric acid catalyst 186 afforded tetrahydroquino-line 187 in 57% yield with 93% ee. Ethoxycarbonylation, deprotection/acylation, and benzylation provided torcetrapib (188) in four steps with 32% overall yield. 

Dugger and co-workers of Pfizer applied the Katritzky methodology for the synthesis of a key intermediate for the CETP inhibitor 35, torcetrapib (CP-529,414). Benzotriazole adduct 31 was prepared in 91% isolated yield in two crops, and racemic tetrahydroquinoline 34 was synthesized in 78%... 

Johns DG, Duffy J, Fisher T, Hubbard BK, Forrest MJ (2012) On- and off-target pharmacology of torcetrapib current understanding and implications for the structure activity relationships (SAR), discovery and development of cholesteryl ester-transfer protein (CETP) inhibitors. Drugs 72 491-507... 

Many other industrial applications at large scale are known. This subject has been comprehensively reviewed by Busacca et al. [37], and we will highlight one example here, the case of torcertrapib - which is a powerful cholesteryl ester transfer protein (CETP) inhibitor invented by Pfizer [38]. The key step in this synthesis - which can be scaled-up to multi-kilograms - is a Buchwald-Hartwig reaction involving very cheap l-chloro-4-trifluoromethylbenzene and a chiral amine in the presence of PdfOAcj and DavePhos (Scheme 2.8). Interestingly, PhB(OH)2 was added in order to activate the catalyst. 

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]. 

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. 

Damon, D. B., Dugger, R. W., Magnus-Aryitey, G., Ruggeri, R. B., Wester, R. T., Tu, M., Abramov, Y. (2006). Synthesis of the CETP inhibitor torcetrapib the resolution route and origin of stereoselectivity in the imininm ion cychzation. Organic Process Research and Development, 10, 464-471. 

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