dalcetrapib and torcetrapib

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer's disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.

Topics: Amides; Anticholesteremic Agents; Benzodiazepines; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Coronary Disease; Esters; Humans; Mendelian Randomization Analysis; Oxazolidinones; Quinolines; Sulfhydryl Compounds

The cholesteryl ester transfer protein (CETP) system moves cholesteryl esters (CE) from high density lipoproteins (HDL) to lower density lipoproteins, i.e. very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) in exchange for triglycerides (TGs). This shuttle process will ultimately form complexes facilitating a bidirectional exchange of CE and TGs, the end process being CE delivery to catabolic sites. The CETP system is generally characteristic of higher animal species; lower species, not provided with this system, have higher and enlarged HDL enriched with apo E, suitable for tissue receptor interaction. Discovery of the CETP system has led to the development of agents interfering with CETP, thus elevating HDL-C and potentially preventing cardiovascular (CV) disease. Activation of CETP leads instead to reduced HDL-C levels, but also to an enhanced removal of CE from tissues. CETP antagonists are mainly small molecules (torcetrapib, anacetrapib, evacetrapib, dalcetrapib) and have provided convincing evidence of a HDL-C raising activity, but disappointing results in trials of CV prevention. In contrast, the CETP agonist probucol leads to HDL-C lowering followed by an increment of tissue cholesterol removal (reduction of xanthomas, xanthelasmas) and positive findings in secondary prevention trials. The drug has an impressive anti-inflammatory profile (markedly reduced interleukin-1β expression). Newer agents, some of natural origin, have additional valuable pharmacodynamic properties. The pharmacological approach to the CETP system remains enigmatic, although the failure of CETP antagonists has dampened enthusiasm. Studies on the system, a crossroad for any investigation on cholesterol metabolism, have however provided crucial contributions and will still be confronting any scientist working on CV prevention.

Topics: Amides; Animals; Anticholesteremic Agents; Benzodiazepines; Cardiovascular Diseases; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Esters; Humans; Lignans; Lipoproteins, HDL; Lipoproteins, VLDL; Oxazolidinones; Probucol; Quinolines; Sulfhydryl Compounds; Triglycerides

Although biomarkers are used as surrogate measures for drug targeting and approval and are generally based on plausible biological hypotheses, some are found to not correlate well with clinical outcomes. Over-reliance on inadequately validated biomarkers in drug development can lead to harm to trial subjects and patients and to research waste. To shed greater light on the process and ethics of biomarker-based drug development, we conducted a systematic portfolio analysis of cholesterol ester transfer protein inhibitors, a drug class designed to improve lipid profiles and prevent cardiovascular events. Despite years of development, no cholesterol ester transfer protein inhibitor has yet been approved for clinical use.. We searched PubMed and Clinicaltrials.gov for clinical studies of 5 known cholesterol ester transfer protein inhibitors: anacetrapib, dalcetrapib, evacetrapib, TA-8995, and torcetrapib. Published reports and registration records were extracted for patient demographic characteristics and study authors' recommendations of clinical usage or further testing. We used Accumulating Evidence and Research Organization graphing to depict the portfolio of research activities and a Poisson model to examine trends. We identified 100 studies for analysis that involved 96 944 human subjects. The data from only 41 201 (42%) of the human subjects had been presented in a published report. For the 3 discontinued cholesterol ester transfer protein inhibitors, we found a pattern of consistently positive results on lipid-modification end points followed by negative results using clinical end points.. Inefficiencies and harms can arise if a biomarker hypothesis continues to drive trials despite successive failures. Regulators, research funding bodies, and public policy makers may need to play a greater role in evaluating and coordinating biomarker-driven research programs.

Topics: Amides; Anticholesteremic Agents; Benzodiazepines; Biomarkers, Pharmacological; Cholesterol Ester Transfer Proteins; Drug Approval; Drug Discovery; Dyslipidemias; Endpoint Determination; Esters; Humans; Lipids; Oxazolidinones; Predictive Value of Tests; Quinolines; Reproducibility of Results; Sulfhydryl Compounds; Time Factors; Treatment Outcome

According to epidemiological studies, there is no clear relationship between the plasma cholesteryl ester transfer protein (CETP) concentration and the development of atherosclerosis in human populations. Although some studies suggest that increased CETP activity relates to undesirable profiles of plasma lipoproteins, promoting an anti-atherogenic plasma lipoprotein profile by drugs that inhibit CETP has not succeeded in preventing atherosclerosis in humans.. This review describes 28 investigations in human populations dealing with plasma CETP, 11 in mice that express human CETP and seven in animals (six in rabbits and one in mice) in which plasma CETP activity was inhibited by drugs.. Present review shows that models in mice expressing human CETP are not illuminating because they report increase as well reduction of atherosclerosis. However, investigations in rabbits and mice that develop severe hypercholesterolaemia clearly indicate that impairment of the plasma CETP activity elicits protection against the development of atherosclerosis; in all of these experiments are attained substantial reductions of the atherogenic lipoproteins, namely, plasma apoB containing lipoproteins.. These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.

Topics: Amides; Animals; Anticholesteremic Agents; Apolipoproteins B; Atherosclerosis; Benzodiazepines; Cholesterol Ester Transfer Proteins; Esters; Humans; Hypercholesterolemia; Mice; Oxazolidinones; Quinolines; Rabbits; Sulfhydryl Compounds

Cholesteryl ester transfer protein (CETP) inhibitors substantially increase the concentration of high-density lipoprotein cholesterol (HDL-C), which may have a possible beneficial effect for cardiovascular disease risk reduction.. Current data regarding the effects of CETP inhibitors on cardiovascular disease risk and possible mechanisms for their effects and safety are presented in this review. Expert commentary: The first CETP inhibitor, torcetrapib, was discontinued because of increased off-target adverse effects (increased serum aldosterone and blood pressure levels). The development program of dalcetrapib and evacetrapib, which were not associated with increased blood pressure, was terminated due to futility (insufficient efficacy) concerning cardiovascular outcomes. Although the failure of torcetrapib has been attributed to specific off-target effects, there are some common characteristics between CETP inhibitors pointing to the possibility that certain adverse effects may be class-specific. The newer CETP inhibitors anacetrapib and TA-8995 have promising effects on lipid profile and metabolism (increase of HDL-C and reduction of both low-density lipoprotein cholesterol and lipoprotein (a) levels), but their cardiovascular effects and safety profile have not yet been confirmed in large outcome trials.

Topics: Amides; Anticholesteremic Agents; Benzodiazepines; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Esters; Humans; Lipids; Lipoprotein(a); Lipoproteins, HDL; Oxazolidinones; Quinolines; Sulfhydryl Compounds

The cholesteryl ester transfer protein (CETP) plays an integral role in the metabolism of plasma lipoproteins. Despite two failures, CETP inhibitors are still in clinical development. We review the genetics of CETP and coronary disease, preclinical data on CETP inhibition and atherosclerosis, and the effects of CETP inhibition on cholesterol efflux and reverse cholesterol transport. We discuss the two failed CETP inhibitors, torcetrapib and dalcetrapib, and attempt to extract lessons learned. Two CETP inhibitors, anacetrapib and evacetrapib, are in phase III development, and we attempt to differentiate them from the failed drugs. Whether pharmacologic CETP inhibition will reduce the risk of cardiovascular disease is one of the most fascinating and important questions in the field of cardiovascular medicine.

Topics: Amides; Anticholesteremic Agents; Atherosclerosis; Benzodiazepines; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials as Topic; Coronary Disease; Esters; Humans; Oxazolidinones; Quinolines; Sulfhydryl Compounds

To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels.. Meta-analysis.. Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke).. 117,411 patients were randomised in a total of 39 trials. All interventions increased the levels of high density lipoprotein cholesterol. No significant effect was seen on all cause mortality for niacin (odds ratio 1.03, 95% confidence interval 0.92 to 1.15, P=0.59), fibrates (0.98, 0.89 to 1.08, P=0.66), or CETP inhibitors (1.16, 0.93 to 1.44, P=0.19); on coronary heart disease mortality for niacin (0.93, 0.76 to 1.12, P=0.44), fibrates (0.92, 0.81 to 1.04, P=0.19), or CETP inhibitors (1.00, 0.80 to 1.24, P=0.99); or on stroke outcomes for niacin (0.96, 0.75 to 1.22, P=0.72), fibrates (1.01, 0.90 to 1.13, P=0.84), or CETP inhibitors (1.14, 0.90 to 1.45, P=0.29). In studies with patients not receiving statins (before the statin era), niacin was associated with a significant reduction in non-fatal myocardial infarction (0.69, 0.56 to 0.85, P=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect (0.96, 0.85 to 1.09, P=0.52). A significant difference was seen between these subgroups (P=0.007). A similar trend relating to non-fatal myocardial infarction was seen with fibrates: without statin treatment (0.78, 0.71 to 0.86, P<0.001) and with all or some patients taking statins (0.83, 0.69 to 1.01, P=0.07); P=0.58 for difference.. Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.

Topics: Amides; Anticholesteremic Agents; Cholesterol Ester Transfer Proteins; Coronary Disease; Esters; Fibric Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, HDL; Myocardial Infarction; Niacin; Oxazolidinones; Quinolines; Randomized Controlled Trials as Topic; Stroke; Sulfhydryl Compounds

High-density lipoprotein cholesterol (HDL-C) contains dozens of apoproteins that participate in normal cholesterol metabolism with a reliance on renal catabolism for clearance from the body. The plasma pool of HDL-C has been an excellent inverse predictor of cardiovascular events. However, when HDL-C concentrations have been manipulated with the use of niacin, fibric acid derivatives, and cholesteryl ester transferase protein inhibitors, there has been no improvement in outcomes in patients where the low-density lipoprotein cholesterol has been well treated with statins. Apolipoprotein L1 (APOL1) is one of the minor apoproteins of HDL-C, newly discovered in 1997. Circulating APOL1 is a 43-kDa protein mainly found in the HDL3 subfraction. In patients with chronic kidney disease (CKD), mutant forms of APOL1 have been associated with rapidly progressive CKD and end-stage renal disease (ESRD). Because mutant forms of APOL1 are more prevalent in African Americans compared to Caucasians, it may explain some of the racial disparities seen in the pool of patients with ESRD in the United States. Thus, HDL-C is an important lipoprotein carrying apoproteins that play roles in vascular and kidney disease.

Topics: Amides; Apolipoprotein A-I; Benzodiazepines; Black or African American; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Esters; Heart Diseases; Humans; Hyperlipoproteinemias; Kidney Diseases; Liver; Niacin; Observational Studies as Topic; Oxazolidinones; Prospective Studies; Quinolines; Randomized Controlled Trials as Topic; Risk; Sulfhydryl Compounds; Triglycerides; White People

To examine the recent advances in our knowledge of cholesteryl ester transfer protein (CETP) inhibitors, heart disease risk reduction, and human lipoprotein metabolism.. CETP inhibitors block the transfer of cholesteryl ester from HDLs to triglyceride-rich lipoproteins (TRLs), thereby raising HDL cholesterol and lowering TRL cholesterol, and in some cases LDL cholesterol. Two CETP inhibitors, dalcetrapib and torcetrapib, have been tested in large clinical trials in statin-treated coronary heart disease patients and have shown no clinical benefit compared to placebo. Anacetrapib and evacetrapib, two potent CETP inhibitors, are now being tested in large clinical trials. Torcetrapib has been shown to decrease the fractional catabolic rate (FCR) of HDL apolipoproteins (apo) A-I and A-II, enhance the FCR of TRL apoB-100 and apoE, and decrease TRL apoB-48 production, but has no significant effects on fecal cholesterol excretion in humans. Anacetrapib also delays the FCR of HDL apoA-I.. CETP inhibitors form a complex between themselves, CETP, and HDL particles, which may interfere with the many physiologic functions of HDL, including reverse cholesterol transport. Available data would suggest that CETP inhibitors will fail as lipid-altering medications to reduce coronary heart disease risk because of interference with normal human HDL metabolism.

Topics: Amides; Anticholesteremic Agents; Apolipoproteins; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials as Topic; Coronary Disease; Esters; Humans; Lipid Metabolism; Protein Binding; Quinolines; Sulfhydryl Compounds; Treatment Failure; Triglycerides

Cholesteryl ester transfer protein (CETP) inhibitors are gaining substantial research interest for raising high density lipoprotein cholesterol levels. The aim of the research was to estimate the efficacy and safety of cholesteryl ester transfer protein inhibitors as novel lipid modifying drugs. Systematic searches of English literature for randomized controlled trials (RCT) were collected from MEDLINE, EBASE, CENTRAL and references listed in eligible studies. Two independent authors assessed the search results and only included the double-blind RCTs by using cholesteryl ester transfer protein inhibitors as exclusively or co-administrated with statin therapy irrespective of gender in enrolled adult subjects. Two independent authors extracted the data by using predefined data fields. Of 503 studies identified, 14 studies met the inclusion criteria, and 12 studies were included into the final meta-analysis. Our meta-analysis revealed that CETP inhibitors increased the HDL-c levels (n = 2826, p<0.00001, mean difference (MD) = 20.47, 95% CI [19.80 to 21.15]) and total cholesterol (n = 3423, p = 0.0002, MD = 3.57, 95%CI [1.69 to 5.44] to some extent combined with a reduction in triglyceride (n = 3739, p<0.00001, MD = -10.47, 95% CI [-11.91 to -9.03]) and LDL-c (n = 3159, p<0.00001, MD = -17.12, 95% CI [-18.87 to -15.36]) irrespective of mono-therapy or co-administration with statins. Subgroup analysis suggested that the lipid modifying effects varied according to the four currently available CETP inhibitors. CETP inhibitor therapy did not increase the adverse events when compared with control. However, we observed a slight increase in blood pressure (SBP, n = 2384, p<0.00001, MD = 2.73, 95% CI [2.14 to 3.31], DBP, n = 2384, p<0.00001, MD = 1.16, 95% CI [0.73 to 1.60]) after CETP inhibitor treatment, which were mainly ascribed to the torcetrapib treatment subgroup. CETP inhibitors therapy is associated with significant increase in HDL-c and decrease in triglyceride and LDL-c with satisfactory safety and tolerability in patients with dyslipidemia. However, the side-effect on blood pressure deserves more consideration in future studies.

Topics: Adult; Amides; Anticholesteremic Agents; Benzodiazepines; Blood Pressure; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Drug Therapy, Combination; Dyslipidemias; Esters; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oxazolidinones; Quinolines; Randomized Controlled Trials as Topic; Sulfhydryl Compounds; Treatment Outcome; Triglycerides

The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP).. Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels. In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction.

Topics: Amides; Animals; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Esters; Humans; Hyperlipidemias; Oxazolidinones; Quinolines; Risk Factors; Sulfhydryl Compounds

Raising HDL cholesterol (HDL-C) has become an attractive therapeutic target to lower cardiovascular risk in addition to statins. Inhibition of the cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, leads to a substantial increase in HDL-C levels. Various CETP inhibitors are currently being evaluated in phase II and phase III clinical trials. However, the beneficial effect of CETP inhibition on cardiovascular outcome remains to be established.. Torcetrapib, the first CETP inhibitor tested in a phase III clinical trial (ILLUMINATE), failed in 2006 because of an increase in all-cause mortality and cardiovascular events that subsequently were attributed to nonclass-related off-target effects (particularly increased blood pressure and low serum potassium) related to the stimulation of aldosterone production. Anacetrapib, another potent CETP inhibitor, raises HDL-C levels by approximately 138% and decreases LDL cholesterol (LDL-C) levels by approximately 40%, without the adverse off-targets effects of torcetrapib (DEFINE study). The CETP modulator dalcetrapib raises HDL-C levels by approximately 30% (with only minimal effect on LDL-C levels) and proved safety in the dal-VESSEL and dal-PLAQUE trials involving a total of nearly 600 patients. Evacetrapib, a relatively new CETP inhibitor, exhibited favorable changes in the lipid profile in a phase II study.. The two ongoing outcome trials, dal-OUTCOMES (dalcetrapib) and REVEAL (anacetrapib), will provide more conclusive answers for the concept of reducing cardiovascular risk by raising HDL-C with CETP inhibition.

Topics: Amides; Animals; Benzodiazepines; Cholesterol Ester Transfer Proteins; Drug Discovery; Esters; Humans; Oxazolidinones; Quinolines; Sulfhydryl Compounds

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.

Topics: Amides; Animals; Biomarkers; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Dyslipidemias; Esters; Humans; Hypolipidemic Agents; Oxazolidinones; Quinolines; Sulfhydryl Compounds; Treatment Outcome

Cholesteryl ester transfer protein (CETP)-inhibiting drugs effectively raise HDL cholesterol. In 2007, the CETP inhibitor torcetrapib unexpectedly showed increased fatality and cardiovascular events, possibly related to increased blood pressure and aldosterone levels caused by torcetrapib. Since then, novel CETP inhibiting drugs have been investigated. This review will discuss the safety of the CETP-inhibiting drugs.. The novel CETP inhibitors dalcetrapib, evacetrapib and anacetrapib did not show harmful effects on blood pressure or aldosterone levels. Ultrasound brachial artery flow-mediated vasodilation, carotid MRI and (18)F-fluordeoxyglucose PET imaging studies, showed that dalcetrapib therapy had neither harmful nor beneficial effects on endothelial function, atherosclerosis progression, or vessel wall inflammation. Recently, the clinical endpoint study investigating dalcetrapib was announced to be terminated early, after the second interim analysis showed that dalcetrapib lacked clinically meaningful efficacy.. Dalcetrapib, evacetrapib and anacetrapib did not show the harmful effects on aldosterone and blood pressure that were exhibited by torcetrapib, indicating that CETP inhibition is well tolerated. So far CETP inhibition did not show beneficial effects on clinical outcome. The phase III study with anacetrapib will give final answers on whether CETP inhibition can reduce cardiovascular events.

Topics: Amides; Animals; Benzodiazepines; Cholesterol Ester Transfer Proteins; Esters; Humans; Oxazolidinones; Quinolines; Safety; Sulfhydryl Compounds

Review literature on the effect of decreasing cholesteryl ester transfer protein (CETP) activity through pharmacological inhibition or modulation in preclinical and clinical settings compared to human CETP deficiency on lipoprotein characteristics, HDL remodelling and function.. Torcetrapib, anacetrapib and dalcetrapib inhibited the heterotypic transfer of cholesteryl ester from HDL to LDL and/or VLDL with similar potency, although the potency of dalcetrapib was time dependent. Homotypic transfer of cholesteryl ester from HDL3 to HDL2 via recombinant human CETP was inhibited by torcetrapib and anacetrapib (CETP inhibitors, CETPi) but not by dalcetrapib (CETP modulator, CETPm). In a hamster model of reverse cholesterol transport, only dalcetrapib increased efflux of fecal sterols from macrophages to feces. In clinical studies, dose-responses of CETPi and CETPm demonstrate qualitative and quantitative changes in HDL and LDL particle composition and distribution.. Recent studies of the CETPi torcetrapib and anacetrapib and the CETPm dalcetrapib have shown differences in the resulting increase in HDL-cholesterol and in the level of HDL remodelling and potential for effective reverse cholesterol transport. Results from ongoing clinical outcomes studies with anacetrapib and dalcetrapib will clarify the relevance of CETP inhibition versus modulation towards HDL remodelling in the treatment of cardiovascular diseases.

Topics: Amides; Animals; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Esters; Humans; Lipoproteins, HDL; Oxazolidinones; Quinolines; Sulfhydryl Compounds

Despite optimal treatment of high low density lipoprotein (LDL) cholesterol with statins many cardiovascular events are not prevented. Additional therapeutic strategies are required to reduce the residual cardiovascular risk. Large epidemiological studies show an inverse correlation between the plasma concentration of high density lipoprotein (HDL) cholesterol and the incidence of cardiovascular events. Under physiological conditions, HDL is vasculoprotective and mediates the reverse cholesterol transport. However, new studies suggest that HDL particles represent a heterogeneous population. Under several pathophysiological conditions, HDL was shown to promote atherogenesis and inflammation. Interventional studies and metaanalyses examining the effect of increasing HDL cholesterol have reported mixed results. Inhibition of cholesteryl ester transfer protein (CETP) is a new and potent strategy to increase HDL concentrations. However, the first CETP-inhibitor torcetrapib increased blood-pressure and increased cardiovascular events despite increasing HDL. The blood-pressure increasing effects are not known for more recently developed CETP inhibitors such as dalcetrapib and anacetrapib nor in patients with genetic CETP deficiency. An increase of HDL cholesterol does not necessarily imply an improvement of the functional properties of HDL such as reverse cholesterol transport. An important open question remains the functional characterization of HDL generated by CETP inhibition. Important current clinical endpoint studies with new CETP inhibitors will elucidate whether increasing HDL by CETP inhibition leads to a reduction of cardiovascular events.

Topics: Amides; Anticholesteremic Agents; Atherosclerosis; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Clofibric Acid; Coronary Artery Disease; Esters; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Life Style; Nicotinic Acids; Oxazolidinones; Quinolines; Randomized Controlled Trials as Topic; Sulfhydryl Compounds; Treatment Outcome

Because high-density lipoprotein cholesterol (HDL-C) levels are inversely related to cardiovascular disease (CVD), raising HDL-C levels would seem intuitively valuable. However, the recent failure of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib to decrease CVD has raised doubts regarding HDL-C raising in general and CETP inhibition in particular for CVD prevention. We briefly discuss the complexity of HDL metabolism, caveats of CETP inhibition, possible mechanisms for torcetrapib's failure, and the potential utility of other CETP inhibitors.. Torcetrapib likely failed because of off-target effects, since other CETP inhibitors, such as dalcetrapib (JTT-705/R1658) or anacetrapib (MK-0859), do not increase blood pressure, a specific pressor effect of tocetrapib that appears to be CETP-independent. In small human trials of short duration, anacetrapib and dalcetrapib appear to improve the lipoprotein profile without obvious adverse effects, so far.. The relationship between HDL metabolism, pharmacologic CETP inhibition, and atherosclerosis requires further elucidation. There seems to be sufficient evidence that evaluation of CETP inhibitors such as dalcetrapib and anacetrapib should proceed, if cautiously, since it remains uncertain whether the increased CVD risk with torcetrapib was related to agent-specific off-target effects or more generally to CETP inhibition as a mechanism to raise HDL.

Topics: Amides; Anticholesteremic Agents; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Esters; Humans; Oxazolidinones; Quinolines; Sulfhydryl Compounds

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.. 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.. 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.

Topics: Amides; Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Clinical Trials, Phase III as Topic; Esters; Humans; Oxazolidinones; Patents as Topic; Quinolines; Sulfhydryl Compounds

Inhibitors of cholesterol ester transfer protein (CETP) have the capacity to increase plasma high-density lipoprotein cholesterol to unprecedented levels. Still, hopes that CETP inhibition could reduce atherosclerosis were dented when the clinical development of one such inhibitor, torcetrapib, was halted because of an unexpected finding of increased cardiovascular and noncardiovascular mortality against a background of elevated blood pressure and plasma aldosterone levels. Recently, evidence has accumulated to show that these untoward effects may have been largely attributable to off-target toxicity of the compound, unrelated to the mechanism of CETP inhibition and not shared by other CETP inhibitors. In this review, we explore the rationale for CETP inhibition, compare the pharmacology of the small molecule CETP inhibitors that reached clinical development, and address the evidence relating to off-target adverse effects.

Topics: Aldosterone; Amides; Animals; Anticholesteremic Agents; Atherosclerosis; Blood Pressure; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Corticosterone; Esters; Humans; Hydrocortisone; Hypercholesterolemia; Oxazolidinones; Quinolines; Sulfhydryl Compounds

Despite reduction in low-density lipoprotein cholesterol, there is still a considerable amount of residual atherosclerosis-related disease. Epidemiological and pathophysiological data strongly favour increasing plasma high-density lipoprotein (HDL) cholesterol levels as antiatherogenic therapy, for example with cholesteryl ester transfer inhibition (CETP). However, negative Phase III studies on clinical end points with the CETP inhibitor torcetrapib challenge the future perspectives of other CETP inhibitors such as JTT-705.. Is there potential for CETP inhibition with JTT-705 after torcetrapib's collapse?. Search of articles in Pubmed citing JTT-705, torcetrapib and anacetrapib, or citing effects of pharmacological HDL-cholesterol raising or CETP inhibition.. There is possibly a future for HDL-cholesterol raising therapies. Phase III clinical studies with either JTT-705 or anacetrapib will determine whether CETP inhibition is beneficial.

Topics: Amides; Animals; Anticholesteremic Agents; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Clinical Trials as Topic; Esters; Humans; Quinolines; Sulfhydryl Compounds

The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein inhibitor torcetrapib has led to considerable doubt about the value of raising high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These results have underscored the intricacy of HDL metabolism, with functional quality perhaps being a more important consideration than the circulating quantity of HDL. As a result, HDL-based therapeutics that maintain or enhance HDL functionality warrant closer investigation. In this article, we review the complexity of HDL metabolism, discuss clinical-trial data for HDL-raising agents, including possible reasons for the failure of torcetrapib, and consider the potential for future HDL-based therapies.

Topics: Amides; Animals; Anticholesteremic Agents; Apolipoprotein A-I; Atherosclerosis; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Esters; Humans; Lipoproteins, HDL; Phospholipids; Quinolines; Sulfhydryl Compounds; Treatment Outcome

Cholesteryl ester transfer protein (CETP) inhibitors are currently being investigated because of their ability to increase high-density lipoprotein cholesterol levels. In various metabolic settings, the relationship between CETP and lipoprotein metabolism is complex and may depend largely on the concentration of triglyceride-rich lipoproteins. Two CETP inhibitors, JTT-705 and torcetrapib, are in an advanced phase of development. Following hopeful intermediate results, a large endpoint study using torcetrapib has just been discontinued due to increased mortality in torcetrapib-treated subjects. In this review we summarize clinical data on the use of CETP inhibitors.

Topics: Amides; Anticholesteremic Agents; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Dyslipidemias; Esters; Female; Humans; Hyperlipoproteinemia Type II; Hypertriglyceridemia; Male; Quinolines; Sulfhydryl Compounds

Epidemiologic studies have shown that the concentration of high-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk. This identifies HDL-C as a potential therapeutic target. Compared with low-density lipoprotein cholesterol (LDL-C)-lowering agents, however, currently available HDL-raising drugs are relatively ineffective. Consequently, recent years have seen considerable efforts expended on identifying new drugs that can raise HDL-C. Cholesteryl ester transfer protein (CETP) plays an important role in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low-density lipoproteins and LDLs. The observation that Japanese populations with CETP deficiency exhibited high levels of HDL-C has led to the concept that drugs targeting CETP activity may elevate HDL-C levels and potentially decrease cardiovascular risk. Support of this proposition has been obtained in rabbits where inhibition of CETP activity is markedly antiatherogenic. Two CETP inhibitors-torcetrapib and JTT-705-are currently in the preliminary stages of clinical development. Initial studies with these drugs in humans show that they substantially increase HDL-C levels and modestly decrease LDL-C levels. Larger, long-term, randomized, clinical end point trials are required to determine whether the beneficial effects of CETP inhibitors on lipoprotein metabolism can translate into reductions in cardiovascular events.

Topics: Amides; Animals; Atherosclerosis; Cardiovascular Diseases; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol, HDL; Cholesterol, LDL; Esters; Glycoproteins; Humans; Quinolines; Risk Factors; Sulfhydryl Compounds; Vaccines

Cholesteryl ester transfer protein (CETP) catalyzes the transfer of cholesteryl ester from high-density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins in exchange for triglyceride, and thereby plays a major role in lipoprotein metabolism. The reciprocal increase in HDL cholesterol (HDL-C) and decrease in low-density lipoprotein cholesterol (LDL-C) associated with CETP deficiency has led to the search for synthetic CETP inhibitors over the past 15 years. Several potent inhibitors have been identified, two of which--JTT-705 and torcetrapib--are undergoing clinical trials. Recent reports that torcetrapib is able to simultaneously raise HDL-C twofold and lower LDL-C by < or = 42% has heightened interest in this new class of agents. Upcoming results from Phase III trials of torcetrapib should provide anatomical measurements of atherosclerosis and thus the first assessment of therapeutic benefit.

Topics: Amides; Atherosclerosis; Carrier Proteins; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Esters; Female; Glycoproteins; Humans; Lipoproteins, HDL; Male; Quinolines; Sulfhydryl Compounds

Innovative pharmacological approaches to raise anti-atherogenic high-density lipoprotein-cholesterol (HDL-C) are currently of considerable interest, particularly in atherogenic dyslipidemias characterized by low levels of HDL-C, such as type 2 diabetes, the metabolic syndrome, and mixed dyslipidemia, but equally among individuals with or at elevated risk for premature cardiovascular disease (CVD). Epidemiological and observational studies first demonstrated that HDL-C was a strong, independent predictor of coronary heart disease (CHD) risk, and suggested that raising HDL-C levels might afford clinical benefit. Accumulating data from clinical trials of pharmacological agents that raise HDL-C levels have supported this concept. In addition to the pivotal role that HDL-C plays in reverse cholesterol transport and cellular cholesterol efflux, HDL particles possess a spectrum of anti-inflammatory, anti-oxidative, anti-apoptotic, anti-thrombotic, vasodilatory and anti-infectious properties, all of which potentially contribute to their atheroprotective nature. Significantly, anti-atherogenic properties of HDL particles are attenuated in common metabolic diseases that are characterized by subnormal HDL-C levels, such as type 2 diabetes and metabolic syndrome. Inhibition of cholesteryl ester transfer protein (CETP), a key player in cholesterol metabolism and transport, constitutes an innovative target for HDL-C raising. In lipid efficacy trials, 2 CETP inhibitors-JTT-705 and torcetrapib-induced marked elevation in HDL-C levels, with torcetrapib displaying greater efficacy. Moreover, both agents attenuate aortic atherosclerosis in cholesterol-fed rabbits. Clinical trial data demonstrating the clinical benefits of these drugs on atherosclerosis and CHD are eagerly awaited.

Topics: Amides; Animals; Atherosclerosis; Biological Transport; Cholesterol; Cholesterol, HDL; Coronary Disease; Esters; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Oxidative Stress; PPAR alpha; PPAR delta; PPAR gamma; Quinolines; Sulfhydryl Compounds

Cholesteryl ester transfer protein (CETP) inhibitors (JTT-705 and torcetrapib) are currently in clinical testing, and significantly raise high-density lipoprotein (HDL) cholesterol levels. Low HDL cholesterol is a significant independent predictor of coronary heart disease (CHD) and HDL raising has been associated with coronary heart disease risk reduction, but there is debate about whether CETP inhibition will reduce coronary heart disease risk.. It has been documented in transgenic mouse models that apolipoprotein (apo) C-I inhibits CETP, and that high mono-unsaturated fat diets prevent the normal stimulation of CETP activity by dietary cholesterol. In rabbits, torcetrapib markedly decreases clearance of HDL cholesteryl ester via an indirect pathway, but has no effect on total plasma cholesteryl ester clearance. In humans, torcetrapib raises HDL apoA-I by modestly decreasing its fractional catabolic rate, while having a very profound effect on raising HDL cholesterol and large alpha-1 migrating HDL particles by more than 50%, with no effect on fecal cholesterol excretion. When JTT-705 at 600 mg/day was given to hypercholesterolemic patients already on pravastatin 40 mg/day, the combination was well tolerated and increases in HDL cholesterol of 28% were noted.. In our view, CETP inhibitors in combination with statins will be profoundly beneficial in reducing human atherosclerosis, primarily because they normalize HDL particles and prevent the transfer of cholesteryl ester from HDL to atherogenic lipoproteins.

Topics: Amides; Animals; Carrier Proteins; Cholesterol Ester Transfer Proteins; Coronary Disease; Esters; Glycoproteins; Humans; Lipid Metabolism; Lipoproteins, HDL; Quinolines; Risk; Sulfhydryl Compounds

Over the past decades, lowering of LDL-cholesterol (LDL-c) levels has been established as the foundation for preventing atherosclerotic disease. It is, however, widely accepted that additional risk reduction has to come from modifying other risk factors than LDL-c. In this context, increasing HDL-cholesterol (HDL-c) levels by pharmacological inhibition of the cholesteryl ester transfer protein (CETP) is currently under intense investigation. Two small-molecule compounds, JTT-705 and Torcetrapib, have been shown to effectively increase HDL-c levels in humans, without inducing clinically significant side effects when used as monotherapy or combined with statins. Whether this approach will translate into a reduction in risk of atherosclerotic disease has not yet been established. Data from studies focusing on genetic CETP deficiency as well as those studying the relationship between CETP plasma levels and risk of atherosclerosis do not provide clear answers. Several long-term clinical studies addressing this crucial issue have recently been initiated, results of which will follow within the next few years. This review focuses on CETP, its role in human lipid metabolism and its relation to atherosclerotic disease. Furthermore, it summarizes the currently available data regarding pharmacological CETP inhibition. Finally, it will highlight a number of issues basic to the considerations of whether CETP inhibition will fulfill its promises.

Topics: Amides; Atherosclerosis; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Esters; Glycoproteins; Humans; Models, Biological; Quinolines; Sulfhydryl Compounds

This review summarizes novel human data on cholesteryl ester-transfer protein (CETP) and atherosclerosis and the possible use of CETP inhibitors in the treatment of dyslipidemia. In addition, it will underline that therapeutic targeting of the high-density lipoprotein (HDL) metabolism entails more than simply observing changes in cholesterol levels of this lipoprotein.. Two pharmacological small-molecule inhibitors of CETP, JTT-705 and torcetrapib, have recently been shown to effectively raise HDL cholesterol in humans without serious side effects when either used as a monotherapy or combined with statins that lower low-density lipoprotein cholesterol. Importantly, prospective data from the Epic-Norfolk study furthermore indicate that elevated CETP concentration in conjunction with elevated triglyceride levels are associated with increased odds for cardiovascular events. Data from the Diabetic Atherosclerosis Intervention Study furthermore show that elevated CETP concentration is associated with increased progression of coronary atherosclerosis in patients with type 2 diabetes who use fenofibrate.. Long-term studies will have to show whether CETP inhibition decreases the risk of atherosclerotic disease in dyslipidemic patients. Increased CETP activity might be detrimental under hypertriglyceridemic conditions which is of importance when considering that a large proportion of patients at increased risk from coronary artery disease exhibit elevated triglyceride levels. Studies into the effects of CETP inhibition in hypertriglyceridemic patients therefore seem warranted. Awaiting the first data on the effect of CETP inhibition on surrogate endpoints for atherosclerosis, this review furthermore outlines that the complexity of HDL metabolism will necessitate a wide variety of studies on many aspects of this intriguing lipoprotein.

Topics: Amides; Animals; Arteriosclerosis; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Esters; Glycoproteins; Humans; Hyperlipidemias; Hypolipidemic Agents; Quinolines; Sulfhydryl Compounds

Subjects with high HDL-C show elevated plasma markers of cholesterol absorption and reduced markers of cholesterol synthesis. We evaluated the effect of dalcetrapib, a cholesteryl ester transfer protein modulator, on markers of cholesterol homeostasis in healthy subjects.. Dalcetrapib was administered daily with or without ezetimibe in a randomized, open-label, crossover study in 22 healthy subjects over three 7-day periods: dalcetrapib 900 mg, ezetimibe 10mg, dalcetrapib 900 mg plus ezetimibe 10mg. Plasma non-cholesterol sterols lathosterol and desmosterol (cholesterol synthesis markers) and campesterol, β-sitosterol and cholestanol (intestinal cholesterol absorption markers) were measured. A hamster model was used to compare the effect of dalcetrapib and torcetrapib with or without ezetimibe on these markers and determine the effect of dalcetrapib on cholesterol absorption.. Dalcetrapib increased campesterol, β-sitosterol, and cholestanol by 27% (p = 0.001), 32% (p < 0.001), and 12% (p = 0.03), respectively, in man (non-cholesterol sterol/cholesterol ratio). Dalcetrapib+ezetimibe reduced campesterol by 11% (p = 0.02); β-sitosterol and cholestanol were unaffected. Lathosterol and desmosterol were unchanged with dalcetrapib, but both increased with ezetimibe alone (56-148%, p < 0.001) and with dalcetrapib + ezetimibe (32-38%, p < 0.001). In hamsters, dalcetrapib and torcetrapib increased HDL-C by 49% (p = 0.04) and 72% (p = 0.003), respectively. Unlike torcetrapib, dalcetrapib altered cholesterol homeostasis towards increased markers of cholesterol absorption; cholesterol synthesis markers were unaffected by either treatment. Dalcetrapib did not change plasma (3)H-cholesterol level but increased (3)H-cholesterol in plasma HDL vs non-HDL, after oral dosing of labeled cholesterol.. Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis.

Topics: Amides; Animals; Anticholesteremic Agents; Azetidines; Biomarkers; Cholestanol; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cricetinae; Cross-Over Studies; Desmosterol; Esters; Ezetimibe; Homeostasis; Humans; Intestinal Absorption; Lipid Metabolism; Male; Mesocricetus; Models, Animal; Phytosterols; Quinolines; Sitosterols; Sulfhydryl Compounds; Switzerland

Efficacy and safety data for dalcetrapib (RO4607381/JTT-705) are presented, following a report of increased mortality and cardiac events with another cholesteryl ester transfer protein inhibitor, torcetrapib, associated with off-target adverse effects (hypertension and the activation of the renin-angiotensin-aldosterone system). The efficacy and clinical safety of dalcetrapib 300, 600, and 900 mg or placebo were assessed (n = 838) in 4 pooled 4-week phase IIa trials (1 monotherapy, n = 193; 3 statin combination, n = 353) and 1 12-week phase IIb trial (with pravastatin, n = 292). Nonclinical safety, assessed by the induction of aldosterone production and aldosterone synthase (cytochrome P450 11B2) messenger ribonucleic acid, was measured in human adrenocarcinoma (H295R) cells exposed to dalcetrapib or torcetrapib. Dalcetrapib increased high-density lipoprotein cholesterol by up to 36% and apolipoprotein A-I by up to 16%. The incidence of adverse events (AEs) was similar between placebo (42%) and dalcetrapib 300 mg (50%) and 600 mg (42%), with more events with dalcetrapib 900 mg (58%) (p <0.05, pooled 4-week studies). Six serious AEs (3 with placebo, 1 with dalcetrapib 300 mg, and 2 with dalcetrapib 600 mg) were considered "unrelated" to treatment. Cardiovascular AEs were similar across treatment groups, with no dose-related trends and no clinically relevant changes in blood pressure or electrocardiographic results. Findings were similar in the 12-week study. In vitro, torcetrapib but not dalcetrapib increased aldosterone production and cytochrome P450 11B2 messenger ribonucleic acid levels. In conclusion, dalcetrapib alone or in combination with statins was effective at increasing high-density lipoprotein cholesterol and was well tolerated, without clinically relevant changes in blood pressure or cardiovascular AEs and no effects on aldosterone production as assessed nonclinically.

Topics: Amides; Anticholesteremic Agents; Cholesterol Ester Transfer Proteins; Coronary Artery Disease; Double-Blind Method; Dyslipidemias; Esters; Female; Humans; Incidence; Male; Middle Aged; Quinolines; Risk Assessment; Risk Factors; Sulfhydryl Compounds

Cholesteryl ester transfer protein (CETP) inhibitors are a new class of therapeutics for dyslipidemia that simultaneously improve two major cardiovascular disease (CVD) risk factors: elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol. However, the detailed molecular mechanisms underlying their efficacy are poorly understood, as are any potential mechanistic differences among the drugs in this class. Herein, we used electron microscopy (EM) to investigate the effects of three of these agents (Torcetrapib, Dalcetrapib and Anacetrapib) on CETP structure, CETP-lipoprotein complex formation and CETP-mediated cholesteryl ester (CE) transfer. We found that although none of these inhibitors altered the structure of CETP or the conformation of CETP-lipoprotein binary complexes, all inhibitors, especially Torcetrapib and Anacetrapib, increased the binding ratios of the binary complexes (e.g., HDL-CETP and LDL-CETP) and decreased the binding ratios of the HDL-CETP-LDL ternary complexes. The findings of more binary complexes and fewer ternary complexes reflect a new mechanism of inhibition: one distal end of CETP bound to the first lipoprotein would trigger a conformational change at the other distal end, thus resulting in a decreased binding ratio to the second lipoprotein and a degraded CE transfer rate among lipoproteins. Thus, we suggest a new inhibitor design that should decrease the formation of both binary and ternary complexes. Decreased concentrations of the binary complex may prevent the inhibitor was induced into cell by the tight binding of binary complexes during lipoprotein metabolism in the treatment of CVD.

Topics: Amides; Cholesterol Ester Transfer Proteins; Esters; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Multiprotein Complexes; Oxazolidinones; Quinolines; Sulfhydryl Compounds

Topics: Amides; Anticholesteremic Agents; Blood Pressure; Blood Viscosity; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Erythrocyte Aggregation; Esters; Humans; Quinolines; Sulfhydryl Compounds; Treatment Failure

Hyperaldosteronism and hypertension were unexpected side effects observed in trials of torcetrapib, a cholesteryl ester-transfer protein (CETP) inhibitor that increases high-density lipoprotein. Given that CETP inhibitors are lipid soluble, accumulate in adipose tissue, and have binding sites for proteins involved in adipogenesis, and that adipocytes are a source of aldosterone, we questioned whether CETP inhibitors (torcetrapib, dalcetrapib, and anacetrapib) influence aldosterone production by adipocytes. Studies were performed using human adipocytes (SW872), which express CETP, and mouse adipocytes (3T3-L1), which lack the CETP gene. Torcetrapib, dalcetrapib, and anacetrapib increased expression of CYP11B2, CYP11B1, and steroidogenic acute regulatory protein, enzymes involved in mineralocorticoid and glucocorticoid generation. These effects were associated with increased reactive oxygen species formation. Torcetrapib, dalcetrapib, and anacetrapib upregulated signal transducer and activator of transcription 3 (STAT3) and peroxisome proliferation-activated receptor-γ, important in adipogenesis, but only torcetrapib stimulated production of chemerin, a proinflammatory adipokine. To determine mechanisms whereby CETP inhibitors mediate effects, cells were pretreated with inhibitors of Nox1/Nox4 [GKT137831; 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione], Nox1 (ML171 [2-acetylphenothiazine]), mitochondria (rotenone), and STAT3 (S3I-201 [2-hydroxy-4-(((4-methylphenyl)sulfonyloxy)acetyl)amino)-benzoic acid]). In torcetrapib-stimulated cells, Nox inhibitors, rotenone, and S3I-201 downregulated CYP11B2 and steroidogenic acute regulatory protein and reduced aldosterone. Dalcetrapib and anacetrapib effects on aldosterone were variably blocked by GKT137831, ML171, rotenone, and S3I-201. In adipocytes, torcetrapib, dalcetrapib, and anacetrapib inhibit enzymatic pathways responsible for aldosterone production through Nox1/Nox4- and mitochondrial-generated reactive oxygen species and STAT3. CETP inhibitors also influence adipokine production. These processes may be CETP independent. Our findings identify novel adipocyte-related mechanisms whereby CETP inhibitors increase aldosterone production. Such phenomena may contribute to hyperaldosteronism observed in CETP inhibitor clinical trials.

Topics: Adipocytes; Aldosterone; Amides; Animals; Cell Line; Cholesterol Ester Transfer Proteins; Esters; Humans; Mice; NADPH Oxidases; Oxazolidinones; Phosphorylation; Quinolines; Reactive Oxygen Species; STAT3 Transcription Factor; Sulfhydryl Compounds

Topics: Amides; Animals; Anticholesteremic Agents; Benzodiazepines; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Disease Models, Animal; Esters; Humans; Lipid Metabolism, Inborn Errors; Mice; Oxazolidinones; Quinolines; Rabbits; Risk Factors; Sulfhydryl Compounds; Treatment Outcome

Topics: Amides; Animals; Anticholesteremic Agents; Benzodiazepines; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Disease Models, Animal; Esters; Humans; Lipid Metabolism, Inborn Errors; Mice; Oxazolidinones; Quinolines; Rabbits; Risk Factors; Sulfhydryl Compounds; Treatment Outcome

Topics: Amides; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Esters; Fibric Acids; Humans; Hypolipidemic Agents; Niacin; Quinolines; Sulfhydryl Compounds

In almost 30 years since the introduction of HMG-CoA reductase inhibitors (statins), no other class of lipid modulators has entered the market. Elevation of high-density lipoprotein-cholesterol (HDL-C) via inhibiting cholesteryl ester transfer protein (CETP) is an attractive strategy for reducing the risk of cardiovascular events in high-risk patients. Transfer of triglyceride and cholesteryl ester (CE) between lipoproteins is mediated by CETP; thus inhibition of this pathway can increase the concentration of HDL-C. Torcetrapib was the first CETP inhibitor evaluated in phase III clinical trials. Because of off-target effects, torcetrapib raised blood pressure and increased the concentration of serum aldosterone, leading to higher cardiovascular events and mortality. Torcetrapib showed positive effects on cardiovascular risk especially in patients with a greater increase in HDL-C and apolipoprotein A-1 (apoA-1) levels. The phase III clinical trial of dalcetrapib, the second CETP inhibitor that has entered clinical development, was terminated because of ineffectiveness. Dalcetrapib is a CETP modulator that elevated HDL-C levels but did not reduce the concentration of low-density lipoprotein cholesterol (LDL-C). Both heterotypic and homotypic CE transfer between lipoproteins are mediated by some CETP inhibitors, including torcetrapib, anacetrapib, and evacetrapib, while dalcetrapib only affects the heterotypic CE transfer. Dalcetrapib has a chemical structure that is distinct from other CETP inhibitors, with a smaller molecular weight and a lack of trifluoride moieties. Moreover, dalcetrapib is a pro-drug that must be hydrolyzed to a pharmacologically active thiol form. Two other CETP inhibitors, anacetrapib and evacetrapib, are currently undergoing evaluation in phase III clinical trials. Both molecules have shown beneficial effects by increasing HDL-C and decreasing LDL-C concentration. The success of anacetrapib and evacetrapib remains to be confirmed upon the completion of phase III clinical trials in 2017 and 2015, respectively. Generally, the concentration of HDL-C has been considered a biomarker for the activity of CETP inhibitors. However, it is not clear whether a fundamental relationship exists between HDL-C levels and the risk of coronary artery diseases. The most crucial role for HDL is cholesterol efflux capacity in which HDL can reverse transport cholesterol from foam cells in atherosclerotic plaques. In view of the heterogeneity in HDL particl

Topics: Amides; Animals; Anticholesteremic Agents; Benzodiazepines; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Coronary Artery Disease; Esters; Humans; Oxazolidinones; Quinolines; Sulfhydryl Compounds

Topics: Acute Coronary Syndrome; Amides; Anticholesteremic Agents; Atherosclerosis; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Early Termination of Clinical Trials; Esters; Humans; Oxazolidinones; Quinolines; Randomized Controlled Trials as Topic; Sulfhydryl Compounds

Topics: Amides; Anticholesteremic Agents; Blood Pressure; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Drug Industry; Esters; Humans; Quinolines; Sulfhydryl Compounds

Topics: Amides; Animals; Anticholesteremic Agents; Azetidines; Cardiovascular Diseases; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials as Topic; Esters; Ezetimibe; Glucose; Humans; Insulin; Lipase; Lipoproteins, HDL; Niacin; Quinolines; Risk Assessment; Risk Factors; Sulfhydryl Compounds

Cholesteryl ester transfer protein (CETP) has been identified as a novel target for increasing HDL cholesterol levels. In this report, we describe the biochemical characterization of anacetrapib, a potent inhibitor of CETP. To better understand the mechanism by which anacetrapib inhibits CETP activity, its biochemical properties were compared with CETP inhibitors from distinct structural classes, including torcetrapib and dalcetrapib. Anacetrapib and torcetrapib inhibited CETP-mediated cholesteryl ester and triglyceride transfer with similar potencies, whereas dalcetrapib was a significantly less potent inhibitor. Inhibition of CETP by both anacetrapib and torcetrapib was not time dependent, whereas the potency of dalcetrapib significantly increased with extended preincubation. Anacetrapib, torcetrapib, and dalcetrapib compete with one another for binding CETP; however anacetrapib binds reversibly and dalcetrapib covalently to CETP. In addition, dalcetrapib was found to covalently label both human and mouse plasma proteins. Each CETP inhibitor induced tight binding of CETP to HDL, indicating that these inhibitors promote the formation of a complex between CETP and HDL, resulting in inhibition of CETP activity.

Topics: Amides; Animals; Anticholesteremic Agents; Blood Proteins; Cholesterol Ester Transfer Proteins; Esters; Humans; Mice; Molecular Structure; Oxazolidinones; Quinolines; Sulfhydryl Compounds

The increased mortality observed with the cholesteryl ester transfer protein inhibitor torcetrapib is partly due to increased aldosterone production and blood pressure. The mechanisms underlying these effects were investigated.. Cytochrome P450 subunit 11B2 (aldosterone synthase), extracellular signal-regulated kinase (p44/42) and voltage-gated Cachannel alpha subunit mRNA profiling, aldosterone production, cytosolic calcium and RNA interference were assessed in adrenocarcinoma human cells (H295R). Telemetry was conducted in spontaneously hypertensive rats.. Torcetrapib and angiotensin II (Ang II) but not dalcetrapib (a structurally different cholesteryl ester transfer protein inhibitor) elevated both cytochrome P450 subunit 11B2 mRNA and aldosterone production in H295R cells at 6 h. At days 1-5, torcetrapib produced a sustained increase of cytochrome P450 subunit 11B2 mRNA, unlike Ang II. Although torcetrapib and Ang II potentiated the effect of 25-OH cholesterol and raised pregnenolone levels, torcetrapib increased neither cytosolic Ca at 5 min nor extracellular signal-regulated kinase1/2 phosphorylation, suggesting initially divergent pathways. Unlike Ang II, torcetrapib steroidogenesis was not affected by Ang II type 1 receptor antagonism or voltage-gated T-type Ca channel antagonism, but was blocked by several L-type Cachannel antagonists. In unbiased genome-wide screening, Ang II and torcetrapib modulated an overlapping but distinct set of genes in H295R cells. Torcetrapib, but not Ang II, upregulated mRNA levels of the L-type Ca channel alpha 1C subunit. In spontaneously hypertensive rat, torcetrapib had a potent hypertensive effect mediated by the L-type Ca channel.. The unique steroidogenic and hypertensive side effects of torcetrapib may be linked and involve voltage-gated L-type Ca channels. Structurally unrelated cholesteryl ester transfer protein inhibitors such as dalcetrapib do not share this effect.

Topics: Adrenal Cortex; Adrenal Gland Neoplasms; Aldosterone; Amides; Angiotensin II; Animals; Anticholesteremic Agents; Blood Pressure; Calcium; Calcium Channels, L-Type; Cell Line, Tumor; Cholesterol Ester Transfer Proteins; Cytochrome P-450 CYP11B2; Cytosol; Enzyme Induction; Esters; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Gene Expression Profiling; Humans; Hypertension; NAV1.1 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Quinolines; Rats; Rats, Inbred SHR; RNA, Small Interfering; Sodium Channels; Structure-Activity Relationship; Sulfhydryl Compounds

Topics: Amides; Anticholesteremic Agents; Blood Pressure; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Esters; Humans; Quinolines; Randomized Controlled Trials as Topic; Sulfhydryl Compounds

Topics: Amides; Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Esters; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oxazolidinones; Predictive Value of Tests; Primary Prevention; Quinolines; Risk Assessment; Risk Factors; Secondary Prevention; Sulfhydryl Compounds

The mechanism by which cholesteryl ester transfer protein (CETP) activity affects HDL metabolism was investigated using agents that selectively target CETP (dalcetrapib, torcetrapib, anacetrapib). In contrast with torcetrapib and anacetrapib, dalcetrapib requires cysteine 13 to decrease CETP activity, measured as transfer of cholesteryl ester (CE) from HDL to LDL, and does not affect transfer of CE from HDL3 to HDL2. Only dalcetrapib induced a conformational change in CETP, when added to human plasma in vitro, also observed in vivo and correlated with CETP activity. CETP-induced pre-β-HDL formation in vitro in human plasma was unchanged by dalcetrapib ≤3 µM and increased at 10 µM. A dose-dependent inhibition of pre-β-HDL formation by torcetrapib and anacetrapib (0.1 to 10 µM) suggested that dalcetrapib modulates CETP activity. In hamsters injected with [³H]cholesterol-labeled autologous macrophages, and given dalcetrapib (100 mg twice daily), torcetrapib [30 mg once daily (QD)], or anacetrapib (30 mg QD), only dalcetrapib significantly increased fecal elimination of both [³H]neutral sterols and [³H]bile acids, whereas all compounds increased plasma HDL-[³H]cholesterol. These data suggest that modulation of CETP activity by dalcetrapib does not inhibit CETP-induced pre-β-HDL formation, which may be required to increase reverse cholesterol transport.

Topics: Amides; Animals; Anticholesteremic Agents; Bile Acids and Salts; Binding Sites; Biological Transport; Cholesterol; Cholesterol Ester Transfer Proteins; Cricetinae; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Esters; High-Density Lipoproteins, Pre-beta; Humans; Oxazolidinones; Quinolines; Sulfhydryl Compounds

Topics: Amides; C-Reactive Protein; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials as Topic; Esters; Heart Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oxazolidinones; Quinolines; Sulfhydryl Compounds

Because cholesteryl ester transfer protein (CETP) inhibition is a potential HDL-raising therapy, interest has been raised in the mechanisms and consequences of CETP activity. To explore these mechanisms and the dynamics of CETP in vitro, a mechanistic mathematical model was developed based upon the shuttle mechanism for lipid transfer. Model parameters were estimated from eight published experimental datasets, and the resulting model captures observed dynamics of CETP in vitro. Simulations suggest the shuttle mechanism yields behaviors consistent with experimental observations. Three key findings predicted from model simulations are: 1) net CE transfer activity from HDL to VLDL and LDL can be significantly altered by changing the balance of homoexchange versus heteroexchange of neutral lipids via CETP; 2) lipemia-induced increases in CETP activity are more likely caused by increases in lipoprotein particle size than particle number; and 3) the inhibition mechanisms of the CETP inhibitors torcetrapib and JTT-705 are significantly more potent than a classic competitive inhibition mechanism with the irreversible binding mechanism having the most robust response. In summary, the model provides a plausible representation of CETP activity in vitro, corroborates strong evidence for the shuttle hypothesis, and provides new insights into the consequences of CETP activity and inhibition on lipoproteins.

Topics: Algorithms; Amides; Animals; Anticholesteremic Agents; Binding Sites; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Computer Simulation; Esters; Humans; Kinetics; Models, Biological; Quinolines; Sulfhydryl Compounds; Triglycerides

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.

Topics: Adrenal Glands; Amides; Animals; Anticholesteremic Agents; Aorta; Blood Pressure; Cholesterol Ester Transfer Proteins; Dose-Response Relationship, Drug; Esters; Heart Rate; Hemodynamics; Male; Polymerase Chain Reaction; Quinolines; Rats; Rats, Inbred SHR; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Sulfhydryl Compounds

Statins effectively lower plasma low-density lipoprotein cholesterol (LDL-C) levels and reduce the risk of vascular events. However, this benefit might be improved by dealing with other vascular risk factors such as high-density lipoprotein cholesterol (HDL-C). It follows that there has been an interest in drugs that raise plasma HDL-C levels. Among these drugs are the cholesteryl ester transfer protein (CETP) inhibitors. The first CETP inhibitor to be evaluated in an event-based trial was torcetrapib. This drug can considerably elevate serum HDL-C levels (e.g., by 72%). However, a recently published trial (ILLUMINATE) showed that torcetrapib used in combination with atorvastatin was associated with significantly more vascular events and deaths than atorvastatin alone. This finding resulted in the discontinuation of the torcetrapib development programme. The cause(s) of the adverse outcome remain speculative. It has been suggested that a significant rise in systolic blood pressure and possibly the quality of the HDL produced may be relevant. Despite this disappointing outcome it seems to be too early to close the book on CETP inhibitors because two other members of this class are being evaluated. These drugs (JTT-705 and anacetrapib) may be devoid of the adverse effect on systolic blood pressure. Eventually only appropriately designed, event-based trials, will settle the issue of whether CETP inhibitors are clinically useful.

Topics: Amides; Blood Pressure; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Drug Design; Drug Therapy, Combination; Esters; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Quinolines; Sulfhydryl Compounds; Up-Regulation

Studies on the relationship between the structure of the benzene moiety of S-(2-(acylamino)phenyl) 2,2-dimethylpropanethioates and CETP inhibitory activity were performed. Substituents on the benzene moiety influenced CETP inhibitory activity in a type and position dependent manner, and electron-withdrawing groups at the 4- or 5-position increased the activity. The most potent compound showed 50% inhibition of CETP activity in human plasma at a concentration of 2 microM.

Topics: Amides; Arteriosclerosis; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Esters; Glycoproteins; Humans; Inhibitory Concentration 50; Protective Agents; Quinolines; Structure-Activity Relationship; Sulfhydryl Compounds