Dalcetrapib,a cholesteryl ester transfer protein modulator

Introduction: Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport by transferring cholesteryl esters from high-density lipoprotein (HDL) to the apolipoprotein B-containing lipoproteins. Inhibition of CETP is a target to increase HDL-cholesterol and potentially reduce atherosclerosis. Dalcetrapib is an orally administered CETP inhibitor developed for the treatment of primary hypercholesterolaemia and mixed hyperlipidaemia.

Areas covered: Areas covered are: mode of action, preclinical development and clinical trials of dalcetrapib, a CETP modulator. The article provides an understanding of the pharmacokinetic and pharmacodynamic characteristics of dalcetrapib and insight into its clinical efficacy and safety. In clinical trials, dalcetrapib produced significant elevations in HDL-cholesterol when taken alone or in combination with statin with no effect on blood pressure or expression of genes involved in the renin–angiotensin–aldosterone system.

Expert opinion: Although dalcetrapib is the least potent CETP inhibitor, it does not impair the formation of CETP-induced pre-β HDL, which might be needed to increase reverse cholesterol transport. While dalcetrapib is well-tolerated and does not show major side effects, the recent interim results of the Phase III dal-OUTCOMES trial have shown the lack of a clinically meaningful benefit, and further testing of the drug has been halted.     

胆固醇酯转移蛋白抑制剂开发

脂代谢异常是动脉粥样硬化和冠心病的重要危险因素,调脂药物通过调控脂质代谢,降低血脂水平,进而降低心血管疾病的发生。胆固醇酯转移蛋白(CETP)抑制剂可明显升高高密度脂蛋白-胆固醇,本文综述几种处于临床研究阶段的CETP抑制剂研究进展。     

胆固醇酯转运蛋白抑制剂的研究进展

目的阐述胆固醇酯转运蛋白 (CETP)抑制剂的研究新进展。方法对近年来国内外相关文献进行整理归纳。结果与结论CETP在协调血脂水平中发挥着重要的作用 ,它与冠心病 (CHD)的发生和发展密切相关 ,可能成为治疗CHD的一个潜在的新靶标 ,因此其抑制剂的研发具有广阔的应用前景。     

胆固醇酯转移蛋白抑制剂Anacetrapib

高密度脂蛋白-胆固醇(HDL-C)低于正常水平是诱发心血管疾病的因素之一,升高较低水平的HDL-C能够降低患心血管疾病的风险.一些代谢疾病,如胰岛素耐受、高三酰甘油血症都会增强胆固醇酯转移蛋白的活性,高活性的胆固醇酯转移蛋白可诱发动脉粥样硬化和增加患心血管疾病的风险.因此,抑制胆固醇酯转移蛋白是治疗动脉粥样硬化症的新靶...     

胆固醇酯转运蛋白的研究进展

阐述了胆固醇酯转运蛋白(CETP)在分子生物学上的研究进展.由于CETP在协调血脂水平中扮演重要的角色,它与冠心病(CHD)的关系十分密切,但CETP究竟是抗动脉粥样硬化(AS)还是致AS的机制还不太明确,需要我们进一步研究从而正确评价其生理病理和临床意义.     

Cholesteryl ester transfer protein inhibitors as high-density lipoprotein raising agents

Background: Not only hypercholesterolemia, but also low levels of high-density lipoprotein cholesterol is a critical risk factor for atherosclerosis-related disease. Therefore, there has been great interest in identifying effective and selective cholesteryl ester transfer protein (CETP) inhibitors that can raise high-density lipoprotein. Recently, Phase III clinical studies of torcetrapib, one of the CETP inhibitors developed by researchers at Pfizer, were unexpectedly terminated because of an increase in cardiovascular events and mortality. Torcetrapib has some compound-specific and off-target effects, such as raising blood pressure and aldosterone, which could affect an increase in cardiovascular events and mortality. Objective: The aim of this review is to provide an update (from 2000 to early 2009) on the patenting activity in the field of CETP inhibitors and the status of the most advanced compounds. Conclusion: Dalcetrapib (JTT-705) and anacetrapib, which have not been reported to have the off-target effects of torcetrapib, are currently in Phase III. They are expected to reveal whether CETP inhibition is beneficial for atherosclerosis-related diseases.     

A peptide inhibitor of cholesteryl ester transfer protein identified by screening a bacteriophage display library

We screened a bacteriophage display library of random decapeptides to identify peptide inhibitors of cholesteryl ester transfer protein (CETP). After affinity selection against CETP, bacteriophage-infected Escherichia coli were plated at clonal density and 36 random clones were isolated. Analysis of the relevant portion of the bacteriophage DNA from a group of 12 clones that had a relatively high affinity for CETP revealed that the corresponding amino acid sequences of the displayed peptides exhibited an. Xaa-Arg-Met-Arg-Tyr-Xaa composite motif. Based on those results, decapeptides from this group were synthesized and one of them, DPI (NH₂-VTWRMWYVPA-COOH), inhibited CETP-catalyzed transfer of cholesteryl esters and triglycerides. Amino- and carboxy-terminal truncations of DPI demonstrated that the original decapeptide could be reduced to a pentapeptide without loss of either its ability to bind to CETP or its ability to inhibit CETP-mediated lipid transfer. That pentapeptide, NH₂-WRMWY-COOH (WRMWY, PNU-107368E), binds directly to CETP and its inhibition is consistent with that of a competitive inhibitor of CETP with a K_i of 164 μm . WRMWY or modified versions of this peptide may be useful in studying the interactions between CETP and plasma lipoproteins.     

Cholesteryl ester transfer protein inhibitors

As well as hypercholesterolaemia, low levels of high-density lipoprotein cholesterol (HDL-C) are critical risk factors for atherosclerosis and coronary heart disease (CHD). Although fibrate, simvastatin and niacin can be used for the treatment of a low HDL-C level, their effects, however, are not wholly satisfactory. Thus, better drugs for the elevation of HDL-C are desired. Among the many methods that may be used to raise HDL-C levels, this review focuses on small molecule inhibitors of cholesteryl ester transfer protein (CETP) and summarises recent patent and journal data.     

Anacetrapib, a cholesteryl ester transfer protein inhibitor

INTRODUCTION: Inhibition of cholesteryl ester transfer protein (CETP) has the ability to increase high-density lipoprotein (HDL)-cholesterol levels and potentially reduce cardiovascular risk. The first CETP inhibitor, torcetrapib, was discontinued due to off-target effects resulting in increased mortality. However, anacetrapib does not appear to exhibit these effects and is being developed as a selective inhibitor of CETP to be orally administered for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. AREAS COVERED: Areas covered are: mode of action, preclinical development and clinical trials of anacetrapib, a CETP inhibitor. The article provides an understanding of the pharmacokinetic and pharmacodynamic characteristics of anacetrapib and insight into its clinical efficacy and safety. In clinical trials, anacetrapib produced dose-dependent elevations in HDL-cholesterol and reductions in low-density lipoprotein (LDL)-cholesterol. Furthermore, anacetrapib has been shown to increase apolipoprotein (apo) A-I and decrease apoB levels. EXPERT OPINION: Anacetrapib is a potent, reversible CETP inhibitor that is not only able to increase HDL-cholesterol, but also further decrease LDL-cholesterol when taken in combination with a statin. Safety and tolerability studies reported to date are promising. The results from Phase III trials investigating the efficacy of anacetrapib for the prevention of major coronary events in patients with atherosclerotic cardiovascular disorders are awaited with interest.     

The potential of cholesteryl ester transfer protein as a therapeutic target

Introduction: Over recent decades, attempts to ascertain the pro-atherogenic nature of plasma cholesteryl ester transfer protein (CETP) and to establish the relevance of its pharmacological blockade as a promising high density lipoproteins-raising and anti-atherogenic therapy have been disappointing.

Areas covered: The current review focuses on CETP as a multifaceted protein, on genetic variations at the CETP gene and on their possible consequences for cardiovascular risk in human populations. Specific attention is given to physiological modulation of endogenous CETP activity by the apoC1 inhibitor. Finally, the rationale behind the need for selection of patients to treat is discussed in the light of recent studies.

Expert opinion: At this stage one can only speculate on the clinical outcome of pharmacological CETP inhibitors in high-risk populations, but recent advances give cause to adjust the expectations from now on. The CETP effect is probably largely influenced by the overall metabolic state, and whether CETP blockade may be relevant or not in promoting cholesterol disposal is still questioned. The possible need for a careful stratification of patients to treat with CETP inhibitors is outlined. Finally, manipulation of CETP activity should be considered with caution in the context of sepsis and infectious diseases.     

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein

AIMS

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP).

METHODS

The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20–45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60–5521 (n = 28) or were treated with a placebo (n = 10).

RESULTS

In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60–5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h.

CONCLUSIONS

BAY 60–5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.     

Cholesteryl ester transfer protein facilitates the movement of water-insoluble drugs between lipoproteins: a novel biological function for a well-characterized lipid transfer protein

This review article addresses the recently discovered finding that cholesteryl ester transfer protein (CETP) can facilitate the transfer of water-insoluble drugs between different lipoprotein subclasses. This protein, which is often referred to as lipid transfer protein I (LTP I), is involved in the lipid regulation of lipoproteins. It is responsible for the facilitated transfer of core lipoprotein lipids, cholesteryl ester and triglycerides, and approximately one-third of the coat lipoprotein lipid, phosphatidylcholine, between different plasma lipoproteins. The human body appears to recognize exogenous water-insoluble drugs as lipid-like particles, which suggests that these compounds may interact with lipoproteins just like endogenous plasma lipids, and thus their transfer between lipoproteins may be facilitated by plasma CETP. Patients with a variety of diseases (i.e. diabetes, cancer, AIDS) often exhibit hypo- and/or hypercholesterolemia and triglyceridemia, commonly referred to as dyslipidemias, which result in changes in their plasma lipoprotein-lipid composition and concentration. The interaction of water-insoluble drugs with these dyslipidemic lipoproteins may be responsible for the differences seen in the pharmacokinetics and pharmacodynamics of the drug within different diseased patient populations. It is possible that these differences may be linked to the ability of CETP to transfer these compounds from one lipoprotein to another. This review examines the current understanding of the relationship between CETP activity and the lipoprotein distribution of a number of compounds (e.g. amphotericin B and cyclosporine A). It further suggests that additional research will expand our understanding of the role of CETP to explain other functions in lipophilic drug distribution and metabolism.     

Atorvastatin affects low density lipoprotein and non-high density lipoprotein cholesterol relations with apolipoprotein B in type 2 diabetes mellitus: modification by triglycerides and cholesteryl ester transfer protein

Objectives: Non-HDL-cholesterol (non-HDL-C) and apolipoprotein (apo) B are proposed as treatment targets. The extent to which statin therapy affects relationships of LDL-C and non-HDL-C with apoB was examined in type 2 diabetes. Methods: Analyses were performed in 217 hypertriglyceridaemic type 2 diabetic patients (Diabetes Atorvastatin Lipid Intervention (DALI) cohort). 61 patients randomized to placebo, 70 to 10 mg atorvastatin daily and 65 – 80 mg atorvastin daily completed follow-up. Results: Baseline fasting LDL-C of 2.42 mmol/l and non-HDL-C of 3.69 mmol/l corresponded to the apoB guideline target of 0.90 g/l. During atorvastatin (10 and 80 mg daily), the LDL-C target was achieved most frequently, and lower LDL-C (2.38 and 2.29 mmol/l) and non-HDL-C (3.24 and 3.19 mmol/l) concentrations corresponded to this apoB goal. Decreases in LDL-C during atorvastatin treatment were negatively related (p < 0.001), but decreases in non-HDL-C were positively related to changes in triglycerides (p < 0.001), independently from decreases in apoB (p < 0.001 for all). Decreases in LDL-C and non-HDL-C were positively associated with decreases in cholesteryl ester transfer protein mass (p < 0.001). Conclusions: During atorvastatin lower LDL-C and non-HDL-C levels correspond to the apoB guideline target, which would favour its use as treatment target.     

Dalcetrapib: a review of Phase II data

Importance of the field: While statins reduce the risk of cardiovascular disease by up to 50%, many patients remain at increased risk due to low levels of high-density lipoprotein cholesterol (HDL-C). Whether pharmacologically raising HDL-C per se with drug therapy will reduce cardiovascular events remains to be determined.

Areas covered in this review: Review of HDL-C-raising compounds, with a focus on cholesteryl ester transfer protein (CETP) inhibitors.

What the reader will gain: An overview of the CETP inhibitor dalcetrapib. Despite 70% increases in HDL-C, development of the CETP inhibitor torcetrapib was halted due to excess mortality, attributed largely to activation of the renin–angiotensin–aldosterone system resulting in hypertensive effects. Development of the CETP inhibitors dalcetrapib and anacetrapib is ongoing. Dalcetrapib has a unique chemical structure and induces a conformational change in CETP rather than forming a non-productive CETP/HDL-C complex as do the other CETP inhibitors. Although dalcetrapib is the least potent CETP inhibitor of the three in terms of CETP activity, the 900-mg dose did not increase blood pressure or raise aldosterone levels over 48 weeks of follow-up. The 600-mg dose of dalcetrapib is moving forward and raises HDL-C by 25 – 30% when used alone or in combination with a statin, with little effect on low-density lipoprotein cholesterol levels.

Take home message: Before regulatory approval is granted, results from the ongoing dal-OUTCOMES trial evaluating the effects of dalcetrapib 600 mg daily over standard statin therapy on mortality and morbidity in > 15,000 high-risk CHD patients will be needed. The Dalcetrapib HDL Evaluation, Atherosclerosis and Reverse Cholesterol Transport (dal-HEART) program also includes three surrogate end point trials, dal-VESSEL, dal-PLAQUE and dal-PLAQUE 2, which will provide further information as to the contribution of CETP to cardiovascular disease.     

Pathophysiology and inhibition of cholesteryl ester transfer protein for prevention of cardiovascular diseases: An update

The enzyme cholesteryl ester transfer protein (CETP), involved in cholesterol metabolism and transportation, is one of the main causes of cardiovascular (CV) disease (CVD). When the CETP concentration is decreased by CETP inhibitors (e.g., anacetrapib, torcetrapib, obicetrapib, etc.), high-density lipoprotein (HDL) particles are formed and low-density lipoprotein (LDL) is decreased along with cholesterol transportation alteration, which reduces the development of atherosclerosis. Here, we discuss the role of CETP inhibitors in reducing well-known ‘bad’ cholesterols and the current status of trials of different CETP inhibitors, their adverse effects, and limitations, as well as the pathophysiology of CETP.     

Prediction of a potentially effective dose in humans for BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically-based pharmacokinetic modelling

AIMS

The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60–5521, in humans.

METHODS

A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60–5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose.

RESULTS

The PBPK approach predicts a greater extent of distribution for BAY 60–5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60–5521 of 51 mg in humans.

CONCLUSION

The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60–5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study.     

Inhibitors of cholesteryl ester transfer protein – a new approach to coronary artery disease

Despite the use of the statins to lower low-density lipoprotein-cholesterol, leading to major reductions in the mortality and morbidity that is associated with coronary artery disease, considerable mortality and morbidity remains. Increasing high-density lipoprotein (HDL)-cholesterol levels has been associated with reduced coronary artery disease mortality and morbidity in several studies. Inhibition of cholesteryl ester transfer protein (CETP) activity leads to increased HDL-cholesterol. In cholesterol-fed rabbits, antibodies against CETP increased HDL-cholesterol and decreased atherosclerotic lesions. In healthy subjects with mild dyslipidaemia, the CETP inhibitors JTT-705 and torcetrapib increased HDL-cholesterol and decreased low-density lipoprotein-cholesterol. Increasing HDL-cholesterol with CETP inhibitors is a new approach to dyslipidaemia that requires further investigation, especially in patients who have coronary artery disease.     

Antiproteinuric therapy decreases LDL-cholesterol as well as HDL-cholesterol in non-diabetic proteinuric patients: relationships with cholesteryl ester transfer protein mass and adiponectin

Objective: Dyslipidemia contributes to increased cardiovascular risk in nephrotic syndrome. We questioned whether reduction in proteinuria not only lowers low-density lipoprotein cholesterol (LDL-C), but also high-density lipoprotein cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP) mass and whether changes in HDL-C were related to changes in plasma adiponectin. Methods: Thirty-two non-diabetic proteinuric patients (12 on statin therapy), were followed during two double blind 6-week periods of placebo and treatment (low sodium + 100mg losartan + 25 mg hydrochlorothiazide). Results: With placebo HDL-C was lower but LDL-C and CETP were not different in proteinuric patients compared with matched controls. LDL-C, HDL-C and CETP decreased upon proteinuria reduction. The decrease in LDL-C correlated with the drop in CETP and the degree of proteinuria reduction. HDL-C also decreased in proportion to proteinuria lowering. Individual changes in HDL-C were correlated with changes in adiponectin. Conclusion: LDL-C lowering upon robust reduction of proteinuria may be affected by changes in plasma CETP mass, but this treatment also decreases HDL-C in relation to the degree of proteinuria reduction. This adverse effect on HDL-C may in part be attributable to changes in adiponectin.     

Mechanistic studies of blood pressure in rats treated with a series of cholesteryl ester transfer protein inhibitors

ILLUMINATE, the Phase 3 clinical trial of morbidity and mortality (M&M) with the cholesteryl ester transfer protein inhibitor (CETPi), torcetrapib (CP‐529,414), was terminated in December 2006 due to an imbalance in all cause mortality. The underlying cause of the M&M remains undetermined. While torcetrapib produced dose‐related increases in blood pressure in clinical trials, the mechanism of the increase in blood pressure is also undetermined. The pressor effects of torcetrapib and structurally related compounds were studied in several pathways involved in blood pressure control. Studies were conducted in rats treated with a series of structurally related molecules (CP‐529,414, CP‐532,623, PF‐868,348, CP‐746,281, CP‐792,485, PF‐868,343, and CE‐308,958). CP‐529,414, CP‐532,623, CP‐868,343, and CP‐792,485 are potent CETP inhibitors; PF‐868,348 is weakly potent and CP‐746,281 and CE‐308,958 are CETP‐inactive. Changes in blood pressure were determined in conscious animals in conjunction with pharmacologic blockade of numerous pressor agents/pathways. Torcetrapib and CP‐532,623 increased blood pressure following both chronic PO and acute IV administration. The CETP‐inactive enantiomer of CP‐532,623, CP‐746,281 failed to raise blood pressure. PF‐868,348, a structural analogue with ～50‐fold lower CETPi activity also displayed pressor activity. Blockade of adrenergic, cholinergic, angiotensin, endothelin, NOS, Rho kinase, and thromboxane pathways failed to attenuate the pressor response. These data demonstrate that the blood pressure activity seen with torcetrapib can be dissociated from CETP inhibitor pharmacology and numerous pharmacology pathways can be discounted in the attempt to understand the molecular basis of the pressor pharmacology. Drug Dev Res 70:2009 © 2009 Wiley‐Liss, Inc.