Inhibition of cholesteryl ester transfer protein (CETP): Different in vitro characteristics of RO4607381/JTT-705 and torcetrapib (TOR)

Niesor, Eric J.; Marck, E. von der; Brousse, María M.; Maugeais, Cyrille

doi:10.1016/j.atherosclerosis.2008.04.024

Cited by 18 publications

(11 citation statements)

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“…In addition, CETP inhibition by this compound was shown to decrease atherosclerosis development in cholesterol-fed rabbits [23]. Dalcetrapib induces a conformational change in CETP, whereas torcetrapib forms a highaffinity nonproductive CETP-HDL complex [25]. In light of the toxic effects of torcetrapib, dalcetrapib was carefully examined for any possible adverse effects.…”

Section: Cholesteryl Ester Transfer Protein Inhibition With Dalcetrapmentioning

confidence: 99%

Safety of CETP inhibition

Duivenvoorden¹,

Fayad²

2012

Current Opinion in Lipidology

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Section: Cholesteryl Ester Transfer Protein Inhibition With Dalcetrapmentioning

confidence: 99%

Safety of CETP inhibition

Duivenvoorden¹,

Fayad²

2012

Current Opinion in Lipidology

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“…Compared to the CETP inhibitors torcetrapib and anacetrapib, dalcetrapib is structurally dissimilar (Figure 2), is less lipophilic than torcetrapib and does not induce formation of a high-affinity ternary complex with CETP and HDL observed in native gels [57]. Dalcetrapib is nevertheless a lipophilic molecule that can bind to lipoproteins [58].…”

Section: Chemistrymentioning

confidence: 99%

“…The absence of lipoproteins in lipoprotein-depleted plasma reduces the IC 50 to 425 nM and suggests binding of dalcetrapib to lipoproteins [57]. Furthermore, preincubation of dalcetrapib An update on the clinical development of dalcetrapib Drug Evaluation future science group in plasma decreases CETP activity potently (IC 50 : 45 ± 2.1 nM for inhibition of CETPmediated transfer of cholesteryl esters, [59]).…”

Section: Pharmacodynamicsmentioning

confidence: 99%

An Update On the Clinical Development of Dalcetrapib (RO4607381), a Cholesteryl Ester Transfer Protein Modulator That Increases HDL Cholesterol Levels

et al. 2012

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CETP is the target of CETP inhibitors such as anacetrapib and the modulator dalcetrapib. Both molecules have entered Phase III clinical trials, with the ultimate goal of reducing cardiovascular events by raising HDL cholesterol. At the 600-mg dose selected for the dal-OUTCOMES study, dalcetrapib is expected to inhibit CETP activity by approximately 30% and raise HDL-C by approximately 30% with limited effects on LDL cholesterol. Importantly, dalcetrapib does not raise blood pressure or aldosterone levels, two effects previously associated with the CETP inhibitor torcetrapib. Dalcetrapib has been well tolerated at the 600-mg dose. In the dal-PLAQUE atherosclerosis imaging study, dalcetrapib reduced the enlargement of total vessel area over time. In May 2012, following the results of the second interim analysis of dal-OUTCOMES, the Data and Safety Monitoring Board recommended stopping the study owing to a lack of clinically significant benefit, which was followed by Roche's (Basel, Switzerland) decision to terminate the study and the dalcetrapib program (dal-HEART). Contrary to anacetrapib, a potent CETP inhibitor that markedly increases HDL cholesterol and significantly reduces LDL cholesterol, dalcetrapib has allowed us to test the hypothesis that an isolated, moderate elevation in HDL cholesterol prevents cardiovascular events.

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“…Torcetrapib, dalcetrapib and anacetrapib compete with one another for binding to CETP; however, the binding site of dalcetrapib is different from that occupied by torcetrapib [355]. The capacity of dalcetrapib to induce formation of a CETP-HDL complex is, however, low at therapeutic plasma levels of the inhibitor [357]. The capacity of dalcetrapib to induce formation of a CETP-HDL complex is, however, low at therapeutic plasma levels of the inhibitor [357].…”

Section: Definitionmentioning

confidence: 99%