Okamoto, H. et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 406, 203-207

Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, JT Inc., Takatsuki, Osaka, Japan.
Nature (Impact Factor: 41.46). 07/2000; 406(6792). DOI: 10.1038/35018119


Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL). This process decreases the level of anti-atherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic. On the other hand, CETP could also be anti-atherogenic, because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver). Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.

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    • "Thus, CETP is involved in cholesterol efflux in RCT, and plays a crucial role in regulating HDL-C levels. These effects were also reported to be induced by a CETP inhibitor as well as congenital CETP deficiency [11], [12]. This suggests that inhibitors of CETP may act as anti-atherogenic agents [13]–[15]. "
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    ABSTRACT: Xanthohumol is expected to be a potent anti-atherosclerotic agent due to its inhibition of cholesteryl ester transfer protein (CETP). In this study, we hypothesized that xanthohumol prevents atherosclerosis in vivo and used CETP-transgenic mice (CETP-Tg mice) to evaluate xanthohumol as a functional agent. Two strains of mice, CETP-Tg and C57BL/6N (wild-type), were fed a high cholesterol diet with or without 0.05% (w/w) xanthohumol ad libitum for 18 weeks. In CETP-Tg mice, xanthohumol significantly decreased accumulated cholesterol in the aortic arch and increased HDL cholesterol (HDL-C) when compared to the control group (without xanthohumol). Xanthohumol had no significant effect in wild-type mice. CETP activity was significantly decreased after xanthohumol addition in CETP-Tg mice compared with the control group and it inversely correlated with HDL-C (%) (P<0.05). Furthermore, apolipoprotein E (apoE) was enriched in serum and the HDL-fraction in CETP-Tg mice after xanthohumol addition, suggesting that xanthohumol ameliorates reverse cholesterol transport via apoE-rich HDL resulting from CETP inhibition. Our results suggest xanthohumol prevents cholesterol accumulation in atherogenic regions by HDL-C metabolism via CETP inhibition leading to apoE enhancement.
    PLoS ONE 11/2012; 7(11):e49415. DOI:10.1371/journal.pone.0049415 · 3.23 Impact Factor
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    • "Dalcetrapib (JTT-705) is the first small molecule that has succeeded in regulating CETP and demonstrating an anti-atherogenic effect in vivo.23 Dalcetrapib is a benzenethiol derivative (Figure 2) that inhibits the CETP-mediated transfer of CE from HDL to apoB-containing lipoproteins in human plasma at an IC50 of 9 μM. "
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    ABSTRACT: Elevated low-density lipoprotein (LDL) cholesterol and lowered high-density lipoprotein (HDL) cholesterol are important risk factors for cardiovascular disease. Accordingly, raising HDL cholesterol induced by cholesteryl ester transfer protein (CETP) inhibition is an attractive approach for reducing the residual risk of cardiovascular events that persist in many patients receiving low-density LDL cholesterol-lowering therapy with statins. The development of torcetrapib, a CETP inhibitor, was terminated due to its adverse cardiovascular effects. These adverse effects did not influence the mechanism of CETP inhibition, but affected the molecule itself. Therefore a CETP modulator, dalcetrapib, and a CETP inhibitor, anacetrapib, are in Phase III of clinical trials to evaluate their effects on cardiovascular outcomes. In the dal-VESSEL (dalcetrapib Phase IIb endothelial function study) and the dal-PLAQUE (safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging) clinical studies, dalcetrapib reduced CETP activity by 50% and increased HDL cholesterol levels by 31% without changing LDL cholesterol levels. Moreover, dalcetrapib was associated with a reduction in carotid vessel-wall inflammation at 6 months, as well as a reduced vessel-wall area at 24 months compared with the placebo. In the DEFINE (determining the efficacy and tolerability of CETP inhibition with anacetrapib) clinical study, anacetrapib increased HDL cholesterol levels by 138% and decreased LDL cholesterol levels by 36%. In contrast with torcetrapib, anacetrapib had no adverse cardiovascular effects. The potential of dalcetrapib and anacetrapib in the treatment of cardiovascular diseases will be revealed by two large-scale clinical trials, the dal-OUTCOMES (efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome) study and the REVEAL (randomized evaluation of the effects of anacetrapib through lipid modification, a large-scale, randomized placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease) study. The dal-OUTCOMES study is testing whether dalcetrapib can reduce cardiovascular events and the REVEAL study is testing whether anacetrapib can reduce cardiovascular events. These reports are expected to be released by 2013 and 2017, respectively.
    Vascular Health and Risk Management 05/2012; 8(1):323-31. DOI:10.2147/VHRM.S25238
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    • "Whereas overexpression of CETP increased atherosclerosis in wild-type and hypercholesterolemic mouse models (de Vries-van der Weij et al, 2009; Plump et al, 1999), a decreased atherosclerotic plaque burden was observed in CETP transgenic hypertriglyceridemic mice and in CETP transgenic mice overexpressing LCAT, despite lower plasma HDL cholesterol levels in these animals (Foger et al, 1999; Hayek et al, 1995). In rabbits (that are expressing CETP), inhibition of CETP by JTT-705 (today called dalcetrapib) attenuated atherosclerosis (Okamoto et al, 2000). Because CETP inhibition may change the composition of HDL particles and give rise to large HDL particles enriched in cholesterol esters, another study sought to characterize the ability of HDL from CETP-deficient subjects to mediate cholesterol efflux from macrophage foam cells (Matsuura et al, 2006). "
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    ABSTRACT: Low high-density lipoprotein (HDL)-cholesterol levels are associated with an increased risk of coronary artery disease (CAD) and myocardial infarction, which has triggered the hypothesis that HDL, in contrast to low-density lipoprotein (LDL), acts as an anti-atherogenic lipoprotein. Moreover, experimental studies have identified potential anti-atherogenic properties of HDL, including promotion of macrophage cholesterol efflux and direct endothelial-protective effects of HDL, such as stimulation of endothelial nitric oxide production and repair, anti-apoptotic, anti-inflammatory and anti-thrombotic properties. Studies in gene-targeted mice, however, have also indicated that increasing HDL-cholesterol plasma levels can either limit (e.g. apolipoprotein A-I) or accelerate (e.g. Scavenger receptor class B type I) atherosclerosis. Moreover, vascular effects of HDL have been observed to be heterogenous and are altered in patients with CAD or diabetes, a condition that has been termed 'HDL dysfunction'. These alterations in biological functions of HDL may need to be taken into account for HDL-targeted therapies and considering raising of HDL-cholesterol levels alone is likely not sufficient in this respect. It will therefore be important to further determine, which biological functions of HDL are critical for its anti-atherosclerotic properties, as well as how these can be measured and targeted.
    EMBO Molecular Medicine 04/2012; 4(4):251-68. DOI:10.1002/emmm.201200224 · 8.67 Impact Factor
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