Old target, but new drug: 2nd generation cetp inhibitor, CKD-508

Lee, J.M.; Lee, Y.J.; Kwon, Nyun-Soo; Ryu, Kyong-Suk

doi:10.1016/j.atherosclerosis.2020.10.813

Cited by 5 publications

(4 citation statements)

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“…These treatments inhibit the PCSK9 mediated degradation of LDLr, increasing the abundance of LDLr and the cellar uptake of LDL-C [57,59]. Moreover, currently being investigated are cholesterylester transfer protein (CETP) inhibitors that reduce the transfer of high density lipoprotein cholesterol (HDL-C), which itself is inversely correlated with risk, to atherogenic LDL-C [60,61], and Bempedoic acid that inhibits cholesterol biosynthesis upstream of HMGCR [62]. A schematic of how these treatments affect cholesterol metabolism is shown in Figure 1.…”

Section: Cholesterol In Health and Diseasementioning

confidence: 99%

The Interdependency and Co-Regulation of the Vitamin D and Cholesterol Metabolism

Warren

McAllister

Morgan

et al. 2021

Cells

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Vitamin D and cholesterol metabolism overlap significantly in the pathways that contribute to their biosynthesis. However, our understanding of their independent and co-regulation is limited. Cardiovascular disease is the leading cause of death globally and atherosclerosis, the pathology associated with elevated cholesterol, is the leading cause of cardiovascular disease. It is therefore important to understand vitamin D metabolism as a contributory factor. From the literature, we compile evidence of how these systems interact, relating the understanding of the molecular mechanisms involved to the results from observational studies. We also present the first systems biology pathway map of the joint cholesterol and vitamin D metabolisms made available using the Systems Biology Graphical Notation (SBGN) Markup Language (SBGNML). It is shown that the relationship between vitamin D supplementation, total cholesterol, and LDL-C status, and between latitude, vitamin D, and cholesterol status are consistent with our knowledge of molecular mechanisms. We also highlight the results that cannot be explained with our current knowledge of molecular mechanisms: (i) vitamin D supplementation mitigates the side-effects of statin therapy; (ii) statin therapy does not impact upon vitamin D status; and critically (iii) vitamin D supplementation does not improve cardiovascular outcomes, despite improving cardiovascular risk factors. For (iii), we present a hypothesis, based on observations in the literature, that describes how vitamin D regulates the balance between cellular and plasma cholesterol. Answering these questions will create significant opportunities for advancement in our understanding of cardiovascular health.

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Section: Cholesterol In Health and Diseasementioning

confidence: 99%

The Interdependency and Co-Regulation of the Vitamin D and Cholesterol Metabolism

Warren

McAllister

Morgan

et al. 2021

Cells

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“…Since the discontinuation of anacetrapib, newer CETP inhibitors are currently undergoing phase III clinical development; in addition to obicetrapib (TA-8995) described below, these also include CKD-508 and MK-8262, all of which are beyond the scope of this meta-analysis [4,44,[64][65][66][67][68].…”

Section: Discussionmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

Rehman,

Yarkoni,

Ilyas

et al. 2024

JCDD

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Background: Atherosclerosis is a multi-factorial disease, and low-density lipoprotein cholesterol (LDL-C) is a critical risk factor in developing atherosclerotic cardiovascular disease (ASCVD). Cholesteryl-ester transfer-protein (CETP), synthesized by the liver, regulates LDL-C and high-density lipoprotein cholesterol (HDL-C) through the bidirectional transfer of lipids. The novelty of CETP inhibitors (CETPis) has granted new focus towards increasing HDL-C, besides lowering LDL-C strategies. To date, five CETPis that are projected to improve lipid profiles, torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have reached late-stage clinical development for ASCVD risk reduction. Early trials failed to reduce atherosclerotic cardiovascular occurrences. Given the advent of some recent large-scale clinical trials (ACCELERATE, HPS3/TIMI55-REVEAL Collaborative Group), conducting a meta-analysis is essential to investigate CETPis’ efficacy. Methods: We conducted a thorough search of randomized controlled trials (RCTs) that commenced between 2003 and 2023; CETPi versus placebo studies with a ≥6-month follow-up and defined outcomes were eligible. Primary outcomes: major adverse cardiovascular events (MACEs), cardiovascular disease (CVD)-related mortality, all-cause mortality. Secondary outcomes: stroke, revascularization, hospitalization due to acute coronary syndrome, myocardial infarction (MI). Results: Nine RCTs revealed that the use of a CETPi significantly reduced CVD-related mortality (RR = 0.89; 95% CI: 0.81–0.98; p = 0.02; I2 = 0%); the same studies also reduced the risk of MI (RR = 0.92; 95% CI: 0.86–0.98; p = 0.01; I2 = 0%), which was primarily attributed to anacetrapib. The use of a CETPi did not reduce the likelihood any other outcomes. Conclusions: Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI.

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“…The blurred mechanism of CETP inhibition led to many questions, such as whether the elevated HDL itself was harmful [134] and whether the decreased levels of non-HDL-C particles allows HDL-C particles to transport more CE out of peripheral tissues [20••]. A new generation CETP inhibitor, such as TA-8899 [129], CKD-508 [135], and MK-8262 [136], which are still under evaluation, may change the picture. Although, CETP inhibitors were developed mainly as an ASCVD therapy, other studies have shown that they reduce diabetes and improve glycemic control [137].…”

Section: Dalcetrapibmentioning

confidence: 99%

Structure-based mechanism and inhibition of cholesteryl ester transfer protein

Han

Zhang

Liu

et al. 2023

Curr Atheroscler Rep

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Purpose of Review Cholesteryl ester transfer proteins (CETP) regulate plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Lipoprotein cholesterol levels correlate with the risk factors for atherosclerotic cardiovascular disease (ASCVD). This article reviews recent research on CETP structure, lipid transfer mechanism, and its inhibition. Recent Findings Genetic deficiency in CETP is associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality. Considering that the elevated CETP activity is a major determinant of the atherogenic dyslipidemia, i.e., pro-atherogenic reductions in HDL and LDL particle size, inhibition of CETP emerged as a promising pharmacological target during the past two decades. CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Although these inhibitors increase in plasma HDL-C levels and/or reduce LDL-C levels, the poor efficacy against ASCVD ended interest in CETP as an anti-ASCVD target. Nevertheless, interest in CETP and the molecular mechanism by which it inhibits CE transfer among lipoproteins persisted. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Summary Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics.

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Old target, but new drug: 2nd generation cetp inhibitor, CKD-508

Cited by 5 publications

References 0 publications

The Interdependency and Co-Regulation of the Vitamin D and Cholesterol Metabolism

The Interdependency and Co-Regulation of the Vitamin D and Cholesterol Metabolism

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

Structure-based mechanism and inhibition of cholesteryl ester transfer protein

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