cholesteryl ester transfer protein inhibitors

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A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Purpose of review . Inhibition of CETP . One approach toward raising serum HDL-C levels is the inhibition of cholesteryl ester-transfer protein (CETP), a plasma protein that promotes the transfer of cholesteryl ester from HDL particles and other lipoprotein fractions to pro-atherogenic apolipoprotein B-containing lipoproteins. The trough inhibition of cholesteryl ester transfer protein (CETP) activity was 65 and 84% at 100 and 300 mg, respectively. Valid for credit through: 3/26/2016. Here, we review the complex relationship between CETP and atherosclerosis based upon the experimental, clinical, and epidemiological studies. PubMed Abstract: Human plasma cholesteryl ester transfer protein (CETP) transports cholesteryl ester from the antiatherogenic high-density lipoproteins (HDL) to the proatherogenic low-density and very low-density lipoproteins (LDL and VLDL). Google Scholar. Cholesteryl ester transfer protein is a central enzyme or transporter in lipid metabolism. Circ Cardiovasc Genet. Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower levels of HDL but raising the levels of proatherogenic LDL and VLDL. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Inhibition of CETP has been shown to raise human plasma HDL cholesterol (HDL-C) levels and is potentially a novel . Assessment of cholesteryl ester transfer protein inhibitors for interaction with proteins involved in the immune response to infection. One approach to raising HDL-C is to inhibit the cholesteryl ester transfer protein (CETP), a plasma protein that promotes transfer of cholesteryl esters from HDL and other lipoprotein fractions. OSTI.GOV Journal Article: Crystal Structures of Cholesteryl Ester Transfer Protein in Complex with Inhibitors However, the detailed molecular mechanisms underlying . The cholesteryl ester transfer protein (CETP) mediates the exchange of lipids between lipoproteins, resulting in the net transfer of cholesteryl ester from high density lipoprotein (HDL) to other lipoproteins and in the subsequent uptake of cholesterol by hepatocytes (summary by Kuivenhoven et al., 1998). Cholesteryl ester transfer protein and its inhibitors. This review appraises recent evidence for a central role of CETP in the action of current lipid-modulating agents with HDL-raising potential, i.e. Resistance arteries and vascular smooth muscle cells (VSMC . To distinguish compound from drug target failure, we . Inhibition of cholesteryl ester transfer protein (CETP) is one approach to increasing HDL-C concentrations. Authors: Christopher P. Cannon, MD Faculty and Disclosures. de Grooth GJ, Kuivenhoven JA, Stalenhoef AFH, et al. Inhibition of CETP . Video. Accordingly, raising HDL cholesterol induced by cholesteryl ester transfer protein (CETP) inhibition is an attractive approach for reducing … Despite two failures, CETP inhibitors are still in clinical development. A peptide consisting of the following amino acid sequence, or an analogue or a fragment thereof, has an inhibitory activity on cholesteryl ester transfer protein: n Glu Asp Thr Ser Pro Glu Asp Lys Met Gln Asp Tyr Val Lys Gln Ala Thr Arg Thr Ala Gln Asp Ala Leu Thr Ser Val Lys. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomized placebo-controlled phase I studies. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study . Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk. A CETP inhibitor is a member of a class of drugs that inhibit cholesterylester transfer protein (CETP). Request PDF | Cholesteryl Ester Transfer Protein Inhibitors | Naturally CETP-deficient animals and genetic cholesteryl ester transfer protein (CETP) deficiency caused by TaqIB polymorphism in . An enhanced understanding of the inhibitor binding site may pro- Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. 1 CETP inhibition is a potential therapeutic strategy to raise HDL levels . Cholesteryl ester transfer protein (CETP) exerts a profound impact on high-density lipoprotein (HDL) metabolism and, consequently, on the risk of atherosclerosis development and cardiovascular mortality. CETP is a plasma glycoprotein that mediates the transfer of cholesteryl esters from HDL to the apoB-containing lipoproteins, with a balanced transfer of triglycerides. This combined effect has made inhibition of CETP an attractive pharmacological approach for reducing the residual incidence of cardiovascular disease (CVD) remaining . Here we will discuss the current status and future prospects of CETP deficiency and CETP inhibitors in the treatment of CHD. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially . 2010; 51:967-974. doi: 10.1194/jlr.M002295 Crossref Medline Google Scholar; 35. The cholesteryl ester transfer protein (CETP) plays an integral role in the metabolism of plasma lipoproteins. US7235259B2 US10/066,091 US6609102A US7235259B2 US 7235259 B2 US7235259 B2 US 7235259B2 US 6609102 A US6609102 A US 6609102A US 7235259 B2 US7235259 B2 US 7235259B2 Authority US United States Hyperaldosteronism and hypertension were unexpected side effects observed in trials of torcetrapib, a cholesteryl ester-transfer protein (CETP) inhibitor that increases high-density lipoprotein. Torcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has been shown to increase HDL cholesterol levels by >50%. de Grooth GJ, Kuivenhoven JA, Stalenhoef AFH, et al. 4 McKenney JM, Davidson MH, Shear CL, Revkin JH. Lancet, 370 (9603) (2007), pp. Title: Cholesteryl Ester Transfer Protein: Pharmacological Inhibition for the Modulation of Plasma Cholesterol Levels and Promising Target for the Prevention of Atherosclerosis. 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 title claims abstract description 319 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13 The presence in human plasma of a protein that promotes bidirectional transfers of neutral lipids (cholesteryl esters and triglycerides) between all lipoprotein particles was first reported in 1978 (1, 2).This protein was identified as cholesteryl ester transfer protein (CETP) and subsequently cloned in 1987 by Drayna et al. (APP,APP) Bloomfield D, Carlson GL, Aditi Sapre BS et al. This combined effect has made inhibition of CETP an attractive pharmacological approach for reducing the residual incidence of cardiovascular disease (CVD) remaining . 2012; 53:1755-1766. doi: 10.1194/jlr.R024075. 9, 10 CETP mediates the heterotypic transfer of neutral lipids (CE and TG) between HDL and apolipoprotein B (apoB . Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. 1907-1914. Cholesteryl ester transfer protein (CETP) catalyses the exchange of cholesteryl ester and triglyceride between HDL and apoB containing lipoprotein particles. The role of CETP in modulating plasma HDL cholesterol levels in humans is well established and there have been significant efforts to develop CETP inhibitors to increase HDL cholesterol for the treatment of coronary artery disease. The concentration of plasma low-density lipoprotein cholesterol (LDL-C) is reduced, while that of total high-density lipoprotein cholesterol (HDL-C) is increased, following inhibition of cholesteryl ester transfer protein (CETP). 2012;53:1755-1766. Because CE originates in HDLs … Cholesteryl ester transfer protein and its inhibitors J Lipid Res. Numerous studies have identified a significant association between the concentration of high-density lipoprotein cholesterol (HDL-C) and the risk of coronary artery diseases (CAD) [1-4].Boosting the concentration of HDL-C thus appears to be an attractive strategy for atherosclerosis risk reduction []. CiteSeerX - Document Details (Isaac Councill, Lee Giles, Pradeep Teregowda): Statins have been shown to decrease cholesteryl ester transfer protein activity (CETP) activity, and rearrange HDL particles. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of . lipophilic inhibitors bind mainly through extensive hydropho-bic interactions with the protein and the shifted cholesteryl ester molecule. Cholesteryl ester transfer protein inhibition enhances endothelial repair and improves endothelial function in the rabbit. Cholesteryl ester transfer protein (CETP) inhibitors (JTT-705 and torcetrapib) are currently in clinical testing and significantly raise high density lipoprotein (HDL) cholesterol levels. Cholesteryl ester transfer-protein modulator and inhibitors and their potential for the treatment of cardiovascular diseases Hisashi ShinkaiCentral Pharmaceutical Research Institute, JT Inc, Osaka, JapanAbstract: Elevated low-density lipoprotein (LDL) cholesterol and lowered high-density lipoprotein (HDL) cholesterol are important risk factors for cardiovascular disease. Cholesteryl ester transfer protein (CETP) inhibitors have previously been shown to increase high density lipoprotein (HDL)-cholesterol and reduce low density lipoprotein (LDL)-cholesterol in humans with varying potency. Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins.It collects triglycerides from very-low-density (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. The hypothesis that CETP inhibition will prevent cardiovascular disease (CVD) was based on the fact that low activity increases HDL cholesterol and decreases LDL cholesterol. Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk. Cholesteryl ester transfer protein and its inhibitors. Cholesteryl ester transfer protein inhibitors for dyslipidemia: focus on dalcetrapib Alyse S Goldberg, Robert A HegeleDepartment of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, CanadaAbstract: Among the noteworthy recent stories in the management and prevention of atherosclerotic cardiovascular disease (CVD) is the saga of the development of . 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