Article

A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits

Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, JT Inc., Takatsuki, Osaka, Japan.
Nature (Impact Factor: 42.35). 01/2000; 406(6792). DOI: 10.1038/35018119

ABSTRACT 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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    • "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 · 8.25 Impact Factor
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    • "Torcetrapib and dalcetrapib decrease CETP activity by different mechanisms. Dalcetrapib forms a bond with cysteine 13 of CETP (Okamoto et al., 2000), most likely located in the lipophilic tunnel of the CETP molecule (Qiu et al., 2007), without inducing the formation of a stable CETP-HDL complex at therapeutic plasma concentrations (Niesor et al., 2008). In contrast, torcetrapib increases the binding affinity of CETP to HDL and the potency for inhibition of CE transfer is correlated with the ability to form a non-productive complex between CETP and HDL (Clark et al., 2006). "
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    ABSTRACT: The association between torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model. Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving torcetrapib 10, 40 or 80 mg kg(-1) day(-1); dalcetrapib 100, 300 or 500 mg(-1) kg day(-1); or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days' treatment with torcetrapib 40 mg kg(-1) day(-1), dalcetrapib 500 mg kg(-1) day(-1) or vehicle was measured by quantitative polymerase chain reaction. Torcetrapib transiently increased mean AP in normotensive rats (+3.7 +/- 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 +/- 0.6 mmHg with 40 mg kg(-1) day(-1) at day 1 (P < 0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas. In contrast to torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein.
    British Journal of Pharmacology 11/2009; 158(7):1763-70. DOI:10.1111/j.1476-5381.2009.00460.x · 4.99 Impact Factor
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    • "Intriguing antiatherogenic effects of CETP inhibition in animal models of atherosclerosis [7] [8] fueled the great anticipation that CETP inhibition raising HDL cholesterol levels would beneficially impact on cardiovascular morbidity and mortality in humans. In the ILLUMINATE trial, however, the CETP inhibitor torcetrapib increased the rate of cardiovascular and non-cardiovascular events, an increase in HDL cholesterol of 72.1% and a decrease in LDL cholesterol of 24.9% notwithstanding [9]. "
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    ABSTRACT: While elevated plasma HDL levels are inversely correlated with cardiovascular events, raising HDL with the CETP inhibitor torcetrapib, however, was associated with increased cardiovascular morbidity and mortality in the ILLUMINATE trial. Whether the deleterious clinical effects of torcetrapib represent a molecule specific off-target effect, a class effect of CETP inhibitors or both is matter of ongoing debate. As such, the aim of the present study was to investigate whether CETP-inhibition with JTT-705, a molecule distinctly different from torcetrapib, impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with type II hyperlipidemia. Eighteen patients were randomized to receive JTT-705 600 mg/d or matching placebo for 4 weeks. Flow-mediated dilation (FMD) was measured using ultrasonography of the brachial artery. HDL-C increased by 26% from 1.14 mmol/l to 1.44 mmol/l (p=0.01) in the JTT-705 group, while triglycerides decreased from 2.52 mmol/l to 1.97 mmol/l (p=0.03). CETP- inhibition with JTT-705, however, did not change FMD (3.1+/-0.6% to 3.6+/-0.4%; p=0.48). Interestingly, in a sub group analysis of patients with lower than median HDL-C (<1.19 mmol/l), FMD increased by 41% in patients vs. patients with higher than median HDL-C (>1.19 mmol/l; p=0.01). Markers of vascular inflammation (CRP, ICAM-1, IL-6, TNF alpha), as well as plasma endothelin-1 levels all remained unchanged throughout the study. In patients with type II hyperlipidemia, CETP inhibition with JTT-705 increased HDL-C and lowered triglycerides but improved endothelial function in the subgroup of patients with low baseline HDL-C levels only.
    Thrombosis Research 10/2008; 123(3):460-5. DOI:10.1016/j.thromres.2008.06.022 · 2.43 Impact Factor
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