Cholesteryl Ester Transfer Protein Inhibitors Research Articles

Associations of genetically determined lipid traits and lipid-modifying agents with the risk of diabetic retinopathy: A Mendelian randomization study

Background and aimsThe evidence that dyslipidemia is associated with hyperglycemia calls for an investigation of whether dyslipidemia, as well as lipid-modifying agents, could affect the subsequent development of diabetic retinopathy (DR). Therefore, we aimed to address these unanswered questions by utilizing Mendelian randomization (MR) analysis. MethodsGenetic variants were selected from the UK Biobank as instruments to serve as proxies for lipid traits [high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (APOA-I) and apolipoprotein B (APOB)]. Univariable and multivariable MR analyses were performed to examine the associations of these lipid traits with DR and different levels of severity of DR. Based on the evidence for the effects of lipids on outcomes, we estimated the causal relevance of cholesteryl ester transfer protein (CETP) inhibitors in severe nonproliferative and proliferative DR using protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) as instruments. ResultsGenetically determined HDL-C levels were inversely associated with the risk of severe nonproliferative DR (OR = 0.70, 95% CI = 0.52–0.94) and proliferative DR (OR = 0.90, 95% CI = 0.83–0.97) in the main analyses utilizing the inverse variance-weighted (IVW) MR method and a couple of sensitivity analyses. No association was noted between genetically proxied CETP inhibitors and DR. ConclusionsThis MR study suggests the casual protective roles of HDL-C in severe nonproliferative DR and proliferative DR, which calls for further studies to confirm these findings. Current lipid-modifying agents acting on HDL-C may not reduce the risk of DR and new treatments are required in the future.

Study of effect modifiers of genetically predicted CETP reduction.

Genetic variants in drug targets can be used to predict the long-term, on-target effect of drugs. Here, we extend this principle to assess how sex and body mass index may modify the effect of genetically predicted lower CETP levelson biomarkers and cardiovascular outcomes. We found sex and body mass index(BMI) to be modifiers of the association between genetically predicted lower CETP and lipid biomarkers in UK Biobank participants. Female sex and lower BMI were associated with higher high-density lipoprotein cholesterol and lower low-density lipoprotein cholesterol for the same genetically predicted reduction in CETP concentration. We found that sex also modulated the effect of genetically lower CETP on cholesterol efflux capacity in samples from the Montreal Heart Institute Biobank. However, these modifying effects did not extend to sex differences in cardiovascular outcomes in our data. Our results provide insight into the clinical effects of CETP inhibitors in the presence of effect modification based on genetic data. The approach can support precision medicine applications and help assess the external validity of clinical trials.

HDL Functions—Current Status and Future Perspectives

Cardiovascular disease (CVD) is the leading cause of death in Western countries. A low HDL-C is associated with the development of CVD. However, recent epidemiology studies have shown U-shaped curves between HDL-C and CVD mortality, with paradoxically increased CVD mortality in patients with extremely high HDL-C levels. Furthermore, HDL-C raising therapy using nicotinic acids or CETP inhibitors mostly failed to reduce CVD events. Based on this background, HDL functions rather than HDL-C could be a novel biomarker; research on the clinical utility of HDL functionality is ongoing. In this review, we summarize the current status of HDL functions and their future perspectives from the findings of basic research and clinical trials.

Effect of lixisenatide on natriuretic peptides in people with type 2 diabetes and recent acute coronary syndrome: The ELIXA trial.

HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly and Company, AstraZeneca, Merck, Novo Nordisk and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, DKSH, Zuellig, Roche and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Kowa, Pfizer, Hanmi and Viatris. EW reports consulting fees from Novartis, AstraZeneca, Boehringer Ingelheim and Bayer. BC reports consulting fees from Amgen, Boehringer-Ingelheim, Cardurion, Corvia, Myokardia and Novartis. SH is an employee and shareholder of Sanofi. JJVMcM has received payments through Glasgow University from work on clinical trials, consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer and Theracos, and personal lecture fees from Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director and Global Clinical Trial Partners (GCTP). LK has received speakers honoraria from Novo, Novartis, Bayer, Boehringer and AstraZeneca. APM reports personal fees from AstraZeneca, Bayer and Novartis for the participation in study committees, outside the present work. MCR reports grants to his institution from Eli Lilly and GlaxoSmithKline, and consulting fees from Eli Lilly, Adocia, Anjii, Sanofi and Xeres. JCT holds the Canada Research Chair in personalized and translational medicine and Université de Montréal endowed research chair in atherosclerosis and reports grants from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, RegenXBio and Sanofi, honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Pharmaceuticals, Pendopharm and Pfizer, minor equity interest in DalCor Pharmaceuticals and is an author of patents on pharmacogenomics-guided CETP inhibition and use of colchicine after myocardial infarction (JCT has waived his rights in the colchicine patents). MAP reports research grant support to his institution from Novartis; is a consultant to: AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, Lexicon, NHLBI CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge and Sanofi; and has equity in DalCor. RD, KD and JLP have no relevant disclosures. The peer review history for this article is available at https://publons.com/publon/10.1111/dom.14954. The data that support the findings of this study are available from the corresponding author upon reasonable request, and subject to conditions determined by the ELIXA steering committee and sponsor. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Association of genetically predicted lipid traits and lipid-modifying targets with heart failure.

To assess the association of genetically predicted lipid traits and lipid-modification via licensed or investigational targets with heart failure (HF). Two-sample Mendelian randomization (MR) study was conducted using summary-level genome-wide association studies (GWASs) from UK Biobank and HERMES Consortium. Genetic variants obtained from UK Biobank GWAS data were selected as instrumental variables to predict the level of lipid traits [LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (ApoB), and apolipoprotein AI (ApoAI)] and lipid-modifying effect of eight drug targets [HMGCR, PCSK9, NPC1L1, PPARA, lipoprotein lipase (LPL), ANGPTL3, APOC3, and cholesteryl ester transfer protein (CETP)]. In this study, we observed that genetically predicted LDL-C, TG, HDL-C or ApoB were significantly related to HF, which were mainly mediated by coronary heart disease (CHD). Drug target MR analyses identified PCSK9, CETP, and LPL as potential targets to prevent HF. The genetic proxy of LDL-C and ApoB increase modified by PCSK9 showed similar evidence in increasing risk of HF (PLDL-C = 1.27*10-4; PApoB = 1.94*10-4); CETP played a role in HF risk via modifying all investigational lipid traits with the strongest evidence though ApoB (P = 5.87*10-6); LPL exerted effects on HF via modifying most lipid traits with the strongest evidence observed via modifying TG (P = 3.73*10-12). This two-sample MR study provided genetic evidence of the associations between lipid traits and HF risk, which were mostly mediated by CHD. Besides, drug target MR studies indicated that PCSK9 inhibition, CETP inhibition, and LPL activation were effective in HF reduction.

CETP Inhibitors: Should We Continue to Pursue This Pathway?

For more than 20years there has been considerable interest in the development of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) by virtue of their ability to raise levels of high-density lipoprotein cholesterol. This review endeavors to integrate existing data from prior clinical trials with emerging data to understand whether there is a pathway forward to develop CETP inhibitors to prevent cardiovascular disease. Large clinical trials have proved disappointing with successive reports of a failure to reduce cardiovascular events. The one clinical development program that did demonstrate a reduction in cardiovascular risk found adipose tissue accumulation and did not proceed for regulatory approval. More recent observations suggest that less CETP activity may prevent cardiovascular events, but due to lipid lowering rather than raising high-density lipoprotein cholesterol. In addition, treatment with CETP inhibitors appears to have a beneficial impact on glycemic control in the setting of diabetes. Advances in the field of CETP inhibition suggest a potentially protective effect on the risk of both cardiovascular disease and diabetes. This has implications for how to best design future clinical development programs and leaves the door open to potentially bring CETP inhibitors to the preventive cardiology clinic.

Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans

The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport.

Evacetrapib Elicits Antitumor Effects on Colorectal Cancer by Inhibiting the Wnt/β-Catenin Signaling Pathway and Activating the JNK Signaling Pathway.

Despite advances in colorectal cancer (CRC) treatment, most advanced CRC patients who experience disease progression after chemotherapy, targeted therapy, and immunotherapy face a situation in which there is no available medicine. Thus, new therapeutic drugs for CRC are urgently needed. Studies have shown that cholesteryl ester transfer protein (CETP) has a vital role in tumor development and is a possible target for CRC therapy. We found that Evacetrapib, a CETP inhibitor, suppressed CRC cell growth by inhibiting the Wnt/β-catenin signaling pathway and activating the c-Jun NH2-terminal kinase (JNK) signaling pathway in CRC. Therefore, Evacetrapib displays an anti-cancer effect and is a possible option for treating CRC.

Cholesteryl Ester Transfer Protein Inhibition Reduces Major Adverse Cardiovascular Events by Lowering Apolipoprotein B Levels.

Cholesteryl ester transfer protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides (TG) between high-density lipoprotein (HDL) particles and TG-rich, apolipoprotein (apo) B-containing particles. Initially, these compounds were developed to raise plasma HDL cholesterol (HDL-C) levels, a mechanism that was previously thought to lower the risk of atherosclerotic cardiovascular disease (ASCVD). More recently, the focus changed and the use of pharmacologic CETP inhibitors to reduce low-density lipoprotein cholesterol (LDL-C), non-HDL-C and apoB concentrations became supported by several lines of evidence from animal models, observational investigations, randomized controlled trials and Mendelian randomization studies. Furthermore, a cardiovascular outcome trial of anacetrapib demonstrated that CETP inhibition significantly reduced the risk of major coronary events in patients with ASCVD in a manner directly proportional to the substantial reduction in LDL-C and apoB. These data have dramatically shifted the attention on CETP away from raising HDL-C instead to lowering apoB-containing lipoproteins, which is relevant since the newest CETP inhibitor, obicetrapib, reduces LDL-C by up to 51% and apoB by up to 30% when taken in combination with a high-intensity statin. An ongoing cardiovascular outcome trial of obicetrapib in patients with ASCVD is expected to provide further evidence of the ability of CETP inhibitors to reduce major adverse cardiovascular events by lowering apoB. The purpose of the present review is to provide an up-to-date understanding of CETP inhibition and its relationship to ASCVD risk reduction.

Longitudinal High-Sensitivity C-Reactive Protein and Longer-Term Cardiovascular Outcomes in Optimally-Treated Patients With High-Risk Vascular Disease

The relation between serial high-sensitivity C-reactive protein (hsCRP) and long-term major cardiovascular events (MACEs; cardiovascular death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) has not been explored in optimally-treated patients with atherosclerotic cardiovascular disease. We tested the hypothesis that longitudinal follow-up hsCRP (repeated measures over time) would associate with 30-month MACE rates. We performed a post hoc analysis of ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibitor with Evacetrapib in Patients with High-Risk for Vascular Outcomes), involving optimally-treated patients with high-risk vascular disease, with available baseline and at least 1 follow-up hsCRP level. Using multivariable Cox proportional hazard models, we determined the association of longitudinal follow-up hsCRP with MACE at 30months among 8,563 patients (aged 64.6 ± 9years, 22% women). Patients with incident MACE (n=961) had higher baseline hsCRP levels (1.77 vs 1.46mg/L, p &lt;0.0001 for patients with and without MACE, respectively) and showed an upward trajectory during follow-up, whereas median hsCRP levels remained &lt;2mg/L at all time points (1.83 vs 1.53mg/L, 1.91 vs 1.53mg/L, 1.76 vs 1.37mg/L, at 3, 12, and 24months, respectively). In a multivariable analysis, higher longitudinal hsCRP levels were independently associated with MACE (hazard ratio [95% confidence interval] per SD 1.19 [1.10 to 1.29], p &lt;0.001), the majority of its individual components and all-cause death. Multivariable models containing longitudinal hsCRP provided improved predictive ability of MACE over baseline hsCRP. In the setting of established medical therapies, longitudinal follow-up hsCRP was independently associated with long-term MACE. In conclusion, these findings suggest that longitudinal hsCRP represents a novel approach of residual cardiovascular risk even when on-treatment hsCRP levels remain &lt;2mg/L.

Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease

Cholesteryl ester transfer protein inhibition (CETP) has been shown to increase levels of high-density lipoprotein cholesterol (HDL-C) and reduce levels of low-density lipoprotein cholesterol (LDL-C). Current LDL-C target attainment is low, and novel phase 3 trials are underway to investigate whether CETP inhibitors result in reduction of cardiovascular disease risk in high-risk patients who may be treated with PCSK9-inhibiting agents. To explore the associations of combined reduction of CETP and PCSK9 concentrations with risk of coronary artery disease (CAD) and other clinical and safety outcomes. Two-sample 2 × 2 factorial Mendelian randomization study in a general population sample that includes data for UK Biobank participants of European ancestry. Separate genetic scores were constructed for CETP and PCSK9 plasma protein concentrations, which were combined to determine the associations of combined genetically reduced CETP and PCSK9 concentrations with disease. Blood lipid and lipoprotein concentrations, blood pressure, CAD, age-related macular degeneration, type 2 diabetes, any stroke and ischemic stroke, Alzheimer disease, vascular dementia, heart failure, atrial fibrillation, chronic kidney disease, asthma, and multiple sclerosis. Data for 425 354 UKB participants were included; the median (IQR) age was 59 years (51-64), and 229 399 (53.9%) were female. The associations of lower CETP and lower PCSK9 concentrations with CAD are similar when scaled per 10-mg/dL reduction in LDL-C concentrations (CETP: odds ratio [OR], 0.74; 95% CI, 0.67 to 0.81; PCSK9: OR, 0.75; 95% CI, 0.71 to 0.79). Combined exposure to lower CETP and PCSK9 concentrations was associated with an additive magnitude with lipids and all outcomes, and we did not observe any nonadditive interactions, most notably for LDL-C (CETP: effect size, -1.11 mg/dL; 95% CI, -1.40 to -0.82; PCSK9: effect size, -2.13 mg/dL; 95% CI, -2.43 to -1.84; combined: effect size, -3.47 mg/dL; 95% CI, -3.76 to -3.18; P = .34 for interaction) and CAD (CETP: OR, 0.96; 95% CI, 0.94 to 1.00; PCSK9: OR, 0.94; 95% CI, 0.91 to 0.97; combined: OR, 0.90; 95% CI, 0.87 to 0.93; P = .83 for interaction). In addition, when corrected for multiple testing, lower CETP concentrations were associated with increased age-related macular degeneration (OR, 1.11; 95% CI, 1.04 to 1.19). Our results suggest that joint inhibition of CETP and PCSK9 has additive effects on lipid traits and disease risk, including a lower risk of CAD. Further research may explore whether a combination of CETP- and PCSK9-related therapeutics can benefit high-risk patients who are unable to reach treatment targets with existing options.

Obicetrapib lowers LDL-C in patients on high intensity statins: Results from the rose trial (NCT04753606)

Background and Aims : As guidelines now recommend lower LDL-C goals, means that many patients require additional lipid lowering therapies (LLT) to attain risk based LDL-C goals despite use of high intensity statins (HIS). Cost and/or efficacy of current LLT options have limited their uptake in clinical practice. Mendelian randomization and RCT trial data support CETP inhibition as a validated target to reduce LDL-C and cardiovascular risk. Safety and efficacy concerns have to date limited the development of CETPi.

Obicetrapib Lowers LDL-C in Patients Taking High Intensity Statins - Results from the ROSE Clinical Trial

Lead Author's Financial Disclosures New Amsterdam Pharma. Study Funding NewAmsterdam Pharma. Background/Synopsis Mendelian randomization studies have predicted that cholesteryl ester transfer protein (CETP) inhibition would reduce the risk of cardiovascular events. This was confirmed in REVEAL; by lowering LDL-C, anacetrapib was associated with a reduction in cardiovascular events. Early studies of the selective CETP inhibitor obicetrapib demonstrated LDL-C lowering up to 45% as monotherapy and 68% in combination with moderate intensity statin therapy. Objective/Purpose To assess the effects of obicetrapib on LDL-C and lipid parameters in patients treated with high intensity statins. Methods Patients (n=120) with an LDL-C ≥70 mg/dL, despite treatment with high intensity statins, were randomized to treatment with obicetrapib 5 or 10 mg or matching placebo for 8 weeks. The primary endpoint was the difference between groups in percent change in LDL-C from baseline to week 8. Secondary endpoints included changes in ApoB, non-HDL-C and HDL-C. Exploratory analyses evaluated differences in Friedewald and preparative ultracentrifugation measurement (PUC) of LDL-C. Safety assessment included biochemistry, vital signs, physical examinations, and adverse events. Results Patients had a median LDL-C of 88 mg/dL at baseline. Compared with placebo, obicetrapib produced greater dose-dependent lowering of LDL-C (up to 50.8%, P<0.0001), which was comparable between PUC and Friedewald measures. Obicetrapib also produced greater lowering of apoB (up to 29.8%, P<0.0001), non-HDL-C (up to 44.4%, P<0.0001), Lp(a) (up to 56.5%, P<0.0001) and raising of HDL-C (up to 165%, P<0.0001) in a dose-dependent fashion compared with placebo. Fewer patients in the obicetrapib arms (26%) experienced treatment-emergent adverse events than in the placebo arm (48%). No patients in either obicetrapib arm experienced a treatment-emergent SAE. There were no clinically significant changes in laboratory parameters, vital signs, or physical examinations in any study group. Conclusions Obicetrapib at doses of 5 and 10 mg produced robust decreases in LDL-C, ApoB, Lp(a) and Non-HDL-C and increases in HDL-C compared to placebo in patients treated with high intensity statins and was safe and well tolerated. New Amsterdam Pharma.

Obicetrapib Lowers LDL-C in Patients Taking High Intensity Statins - Results from the ROSE Clinical Trial

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> NewAmsterdam Pharma. <h3>Background/Synopsis</h3> Mendelian randomization studies have predicted that cholesteryl ester transfer protein (CETP) inhibition would reduce the risk of cardiovascular events. This was confirmed in REVEAL; by lowering LDL-C, anacetrapib was associated with a reduction in cardiovascular events. Early studies of the selective CETP inhibitor obicetrapib demonstrated LDL-C lowering up to 45% as monotherapy and 68% in combination with moderate intensity statin therapy. <h3>Objective/Purpose</h3> To assess the effects of obicetrapib on LDL-C and other lipid parameters in patients treated with high intensity statins. <h3>Methods</h3> Patients (n=120) with an LDL-C ≥70 mg/dL, despite treatment with high intensity statins, were randomized to treatment with obicetrapib 5 or 10mg or matching placebo for 8 weeks. The primary endpoint was the difference between groups in percent change in LDL-C from baseline to week 8. Secondary endpoints included changes in ApoB, non-HDL-C and HDL-C. Exploratory analyses evaluated differences in Friedewald and preparative ultracentrifugation measurement (PUC) of LDL-C. Safety assessment included biochemistry, vital signs, physical examinations, and adverse events. <h3>Results</h3> Patients had a median LDL-C of 88mg/dL at baseline. Compared with placebo, obicetrapib produced greater dose-dependent lowering of LDL-C (up to 50.8%, P<0.0001), which was comparable between PUC and Friedewald measures. Obicetrapib also produced greater lowering of apoB (up to 29.8%, P<0.0001) and non-HDL-C (up to 44.4%, P<0.0001) and raising of HDL-C (up to 165%, P<0.0001) in a dose-dependent fashion compared with placebo. (Table) Fewer patients in the obicetrapib arms (26%) experienced treatment emergent adverse events than in the placebo arm (48%). No patients in either obicetrapib arm experienced a treatment emergent SAE. There were no clinically significant changes in laboratory parameters, vital signs, or physical examinations in any study group. <h3>Conclusions</h3> Obicetrapib at doses of 5 and 10mg produced robust decreases in LDL-C, ApoB and Non-HDL-C and increases in HDL-C compared to placebo in patients treated with high intensity statins and was safe and well tolerated.

Structure of New Ferroverdins Recruiting Unconventional Ferrous Iron Chelating Agents

Ferroverdins are ferrous iron (Fe2+)-nitrosophenolato complexes produced by a few Streptomyces species as a response to iron overload. Previously, three ferroverdins were identified: ferroverdin A, in which three molecules of p-vinylphenyl-3-nitroso-4-hydroxybenzoate (p-vinylphenyl-3,4-NHBA) are recruited to bind Fe2+, and Ferroverdin B and Ferroverdin C, in which one molecule of p-vinylphenyl-3,4-NHBA is substituted by hydroxy-p-vinylphenyl-3,4-NHBA, and by carboxy-p-vinylphenyl-3,4-NHBA, respectively. These molecules, especially ferroverdin B, are potent inhibitors of the human cholesteryl ester transfer protein (CETP) and therefore candidate hits for the development of drugs that increase the serum concentration of high-density lipoprotein cholesterol, thereby diminishing the risk of atherosclerotic cardiovascular disease. In this work, we used high-resolution mass spectrometry combined with tandem mass spectrometry to identify 43 novel ferroverdins from the cytosol of two Streptomyces lunaelactis species. For 13 of them (designated ferroverdins C2, C3, D, D2, D3, E, F, G, H, CD, DE, DF, and DG), we could elucidate their structure, and for the other 17 new ferroverdins, ambiguity remains for one of the three ligands. p-formylphenyl-3,4-NHBA, p-benzoic acid-3,4-NHBA, 3,4-NHBA, p-phenylpropionate-3,4-NHBA, and p-phenyacetate-3,4-NHBA were identified as new alternative chelators for Fe2+-binding, and two compounds (C3 and D3) are the first reported ferroverdins that do not recruit p-vinylphenyl-3,4-NHBA. Our work thus uncovered putative novel CETP inhibitors or ferroverdins with novel bioactivities.

Synthesis and Molecular Modeling of Novel 3,5-Bis(trifluoromethyl) benzylamino Benzamides as Potential CETP Inhibitors.

There is an alarming spread of cases of lipid disorders in the world that occur due to harmful lifestyle habits, hereditary risk influences, or as a result of other illnesses or medicines. Cholesteryl Ester Transfer Protein (CETP) is a 476-residue lipophilic glycoprotein that helps in the transport of cholesteryl ester and phospholipids from the atheroprotective HDL to the proatherogenic LDL and VLDL. Inhibition of CETP leads to elevation of HDL cholesterol and reduction of LDL cholesterol and triglycerides; therefore, it is considered a good target for the treatment of hyperlipidemia and its comorbidities. In this research, synthesis, characterization, molecular modeling, and biological evaluation of eight 3,5-bis(trifluoromethyl)benzylamino benzamides 9a-d and 10a-d were carried out. The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. They were biologically tested in vitro to estimate their CETP inhibitory activity. These compounds offered inhibitory effectiveness ranging from 42.2% to 100% at a concentration of 10 μM. Compounds bearing unsubstituted three aromatic rings (9a) or ortho-CF3 substituted (9b) were the most effective compounds among their analogs and showed IC50 values of 1.36 and 0.69 μM, respectively. The high docking scores of 9a-d and 10a-d against 4EWS imply that they might be possible CETP inhibitors. Pharmacophore mapping results demonstrate that the series approves the fingerprint of CETP active inhibitors and therefore explains their high binding affinity against CETP binding site. This work concludes that 3,5-bis(trifluoromethyl)benzylamino benzamides can serve as a promising CETP inhibitor lead compound.

Abstract 118: Cholesteryl Ester Transfer Protein Overrides The Protective Effect Of APOA1 On Arterial APOB Lipoprotein Trapping And Atherosclerosis Progression In A Mouse Model Of Type 1 Diabetes

Despite the benefits of LDL-cholesterol-reducing medications, patients with type 1 diabetes (T1D) continue to have an increased risk of incident CVD. Preclinical and clinical observations indicate that triglyceride-rich lipoproteins (TRLs) and their remnants may contribute significantly to CVD risk in T1D. Recently, we have shown that diabetes increases levels of atherogenic TRL remnants and that improvement of remnant clearance halts atherosclerosis in a mouse model of T1D. Cholesteryl ester transfer protein (CETP), which is normally absent in mice, links metabolism of TRLs to that of HDL by mediating the transfer of cholesteryl ester from HDL to VLDL and other APOB-containing lipoproteins in exchange for triglycerides. We hypothesized that CETP impairs the atheroprotective effects of APOA1 by altering TRL and HDL metabolism in diabetes. To test this hypothesis, we developed a virally-induced T1D mouse model expressing the human APOA1 transgene ( APOA1 Tg , Ldlr –/– ). Cohorts of these mice were injected with a liver-targeted adeno-associated virus to express human CETP, and the effects on lipoproteins, plasma apolipoproteins, HDL particle concentrations (HDL-P), and atherosclerosis in the presence and absence of diabetes were determined. This mouse model exhibits an HDL profile similar to humans, with small, medium and large HDL-P, whereas wildtype ( Ldlr -/- ) littermates have only one sized HDL-P. Expression of the APOA1 transgene significantly suppressed diabetes-accelerated necrotic core expansion and accumulation of APOB and APOE in the aortic sinus (compared to wildtype Ldlr -/- mice), while CETP impaired the protective effect of APOA1 on these parameters in diabetic APOA1 Tg , Ldlr –/– mice (n= 22-30, p &lt; 0.05). Further characterization of plasma lipoproteins and apolipoproteins by targeted mass spectrometry, FPLC and differential ion mobility analysis indicated that CETP leads to smaller TRL remnant particles, increases triglyceride content in HDL, lower levels of plasma APOA1 and reduction in large HDL-P under diabetic conditions (n= 8-10, p &lt; 0.05). Our results are consistent with the proposal that inhibition of CETP might be cardioprotective in the setting of T1D and highlight the close links between TRL and HDL metabolism in diabetes.

The effect of CETP inhibitors on new-onset diabetes: a systematic review and meta-analysis.

Despite the increasing prevalence of type 2 diabetes mellitus (T2DM), limited pharmacologic options are available for prevention. Cholesteryl ester transfer protein inhibitors (CETPis) have been studied primarily as a therapy to reduce cardiovascular disease, but have also been shown to reduce new-onset diabetes. As new trial data have become available, this meta-analysis examines the effect of CETP inhibitors on new-onset diabetes and related glycaemic measures. We searched MEDLINE, EMBASE, and Cochrane databases (all articles until 4 March, 2021) for randomised controlled trials (RCT)≥1-year duration, with at least 500 participants, comparing CETPi to placebo, and that reported data on new-onset diabetes or related glycaemic measures [haemoglobin A1C (HbA1C), fasting plasma glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)]. A fixed effects meta-analysis model was applied to all eligible studies to quantify the effect of CETPi therapy on new-onset diabetes. Four RCTs (n=75102) were eligible for quantitative analysis of the effect of CETPi on new-onset diabetes. CETPis were found to significantly decrease the risk of new-onset diabetes by 16% (RR: 0.84; 95% CI: 0.78, 0.91; P&lt; 0.001), with low between-trial heterogeneity (I2=4.1%). Glycaemic measures were also significantly improved or trended towards improvement in those with and without diabetes across most trials. Although RCTs have shown mixed results regarding the impact of CETPi on cardiovascular disease, they have shown a consistent reduction in the risk of new-onset diabetes with CETPi therapy. Future trials of CETPis and potentially other HDL-raising agents should therefore specify new-onset diabetes and reversal of existing T2DM as secondary endpoints.

Thiomethylphenyl Benzenesulfonamides as Potential Cholesteryl Ester Transfer Protein Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

Background: The number of lipid disorders cases has risen dramatically around the world as a result of poor dietary habits, hereditary risk factors, or other diseases or medicines. Cholesteryl ester transfer protein (CETP) is a 476 amino acid lipophilic glycoprotein that helps transport cholesteryl esters and phospholipids from proatherogenic LDL and VLDL to atheroprotective HDL. CETP inhibition increases HDL cholesterol, lowers LDL cholesterol and triglycerides, rendering it a promising therapy option for hyperlipidemia and its comorbidities. Methods: In this research, fourteen benzenesulfonamides 7a-7g and 8a-8g were synthesized and identified using 1H-NMR, 13C-NMR, IR and MS. The in vitro biological evaluation of 7a- 7g and 8a-8g revealed CETP inhibitory activities ranging from 15.6 to 100% at 10 μM concentration. Results: Four aromatic rings compounds bearing either m-CH3 (8c) or p-Cl (8g) were the most potent compounds with 100% CETP inhibition, while the most active compound was 7c bearing three aromatic rings and m-CH3 with an IC50 of 0.12 μM. LibDock displayed that benzenesulfonamides can form hydrophobic interactions with the side chains of Leu129, Cys13, Ala202, Val198, Leu217 and Ile215 and participate in п-п stacking with Phe441, Phe197 and Arg201 in the binding pocket of CETP. Conclusion: Pharmacophore mapping showed significant matching with the pharmacophoric features of Hypo4/8 and shape-complemented Hypo4/8 of CETP inhibitors for potent compounds.

Protecting-group-free enantioselective tandem allylic substitution of o-phenylenediamines and o-aminophenols

A protecting-group-free enantioselective tandem allylic substitution of o-phenylenediamines and o-aminophenols is realized for the first time with a Pd-WingPhos catalyst, providing expedient access to a series of chiral vinyl-substituted heterocycles in excellent ee and yields under mild reaction conditions. The protocol is applied successfully to the synthesis of a cholesteryl ester transfer protein (CETP) inhibitor.