Cholesteryl ester transfer protein inhibitor

SJ Coval, MA Conover, R Mierzwa, A King, MS Puar. Wiedendiol-A and B, cholesteryl ester transfer protein inhibitors from the marine sponge Xestesponogia wiedenmayeni. Bioorg Med Chem Lett 5 605-610, 1995. 

MZ Kuo, RJ Zielinski, JI Cialdella, CK Marschke, MJ Dupui s, GP Li, DA Klooster-man, CH Spilman, VP Marshall. Discovery, isolation, structure elucidation and biosynthesis of U-106305, a cholesteryl ester transfer protein inhibitor from UC11136. J Am Chem Soc 117 10629-10634, 1995. 

Prakash C, Chen W, Rossulek M, Johnson K, Zhang C, O Connell T, Potchoiba M, Dalvie D. Metabolism, pharmacokinetics, and excretion of a cholesteryl ester transfer protein inhibitor, torcetrapib, in rats, monkeys, and mice Characterization of unusual and novel metabolites by high-resolution liquid chromatography-tandem mass spectrometry and IH nuclear magnetic resonance. Drug Metab Dispos 2008a 36 2064-2079. 

Huang Z, Inazu A, Nohara A, Higashikata T, Mabuchi H. Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia. Clin Sci 2002 103 587-594. 

CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS fSEDA-32, 817 SEDA-33, 929 SEDA>34, 723 SEDA-35, 810] ... 

Discovery of the cholesteryl ester transfer protein inhibitor anacetrapib... 

Apohpoproteins carry out several roles (1) they can form part of the stmcture of the hpoprotein, eg, apo B (2) they are enzyme cofactors, eg, C-11 for lipoprotein hpase, A-1 for lecithinicholesterol acyltransferase, or enzyme inhibitors, eg, apo A-11 and apo C-111 for lipoprotein hpase, apo C-1 for cholesteryl ester transfer protein and (3) they act as hgands for interaction with lipopro-... 

Tabata N, Tomoda H, Omura S (1999) Ferroverdins, Inhibitors of Cholesteryl Ester Transfer Protein Produced by Streptomyces sp. WK-5344. II. Structure Elucidation. J Antibiotics 52 1108... 

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. 

Paulsen, H., Antons, S., Brandes, A., et al. (1999) Stereoselective Mukaiyama-Michael/Michael/Aldol domino cyclization as the key step in the synthesis of penta-substituted arenes an efficient access to highly active inhibitors of cholesteryl ester transfer protein (CETP). Angew. Chem. Int. Ed. 38, 3373-3375. 

IV. SCREENING FOR INHIBITORS OF CHOLESTERYL ESTER TRANSFER PROTEIN... 

H Tomoda, N Tabata, R Masuma, SY Si, S Omura. Erabulenols A and B, inhibitors of cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. I. Production, isolation and biological properties. J Antibiot 51 618-623, 1998. 

N Tabata, H Tomoda, S Omura. Ferroverdins, potent inhibitors of cholesteryl ester transfer protein, produced by Streptomyces sp. WK-5344. II. Structure elucidation. J Antibiot 52 1108-1113, 1999. 

Upjohn scientists isolated a potent inhibitor of the cholesteryl ester transfer protein U-106305. The high-resolution mass spectrum indicated that the formula was C28H41NO, and the spectrum had 27 distinct resonances (including one pair of equivalent carbons at 8 20.02). DEPT spectra indicated the multiplicities given in the following table ... 

Hedge VR, Dai P, Patel M, Das PR, Wang S, Puar MS. A depsipeptide fungal metabolite inhibitor of cholesteryl ester transfer protein. Bioorg Med Chem Lett 8 1277-1280, 1998. 

Decreases in plasma VLDL primarily result from the ability of these compounds to stimulate the activity of lipoprotein lipase, the enzyme responsible for removing triglycerides from plasma VLDL (Fig. 30.5). Additionally, fibrates can lower VLDL levels through PPARa-mediated stimulation of fatty acid oxidation, inhibition of triglyceride synthesis, and reduced expression of apoC-lll. This latter effect enhances the action of lipoprotein lipase, because apoC-lll normally serves as an inhibitor of this enzyme. Favorable effects on FIDL levels appear to be related to increased transcription of apoA-l and apoA-ll as well as a decreased activity of cholesteryl ester transfer protein. 

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... 

Oral cholesteryl ester transfer protein (CETP) inhibitors for treating coronary artery disease 06JMC1. 

C28H41NO, Mr 407.61, oil, [a]o -270° (CHCI3). Inhibitor of cholesteryl ester transfer protein (CETP), a key factor of lipid metabolism, that controls the transformation of HDL- into LDL-lipids, from cultures of a Streptoverticillium strain. The methylene groups of the quinquecyclopropane units originate biosynthetically from methionine. U. is structurally closely related to FR 900848. 

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. 

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. 

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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