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Stanford BIO 230 - Study Notes

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PerspectiVeOral Cholesteryl Ester Transfer Protein (CETP) Inhibitors: A Potential New Approach forTreating Coronary Artery DiseaseJames A. Sikorski†DiscoVery Medicinal Chemistry, AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, Georgia 30004ReceiVed April 25, 2005IntroductionCholesteryl ester transfer protein (CETP), a plasma glyco-protein, mediates the transfer of neutral lipids in the bloodamong various lipoproteins.1,2Because of their poor watersolubility, neutral lipids such as triglycerides (TG), freecholesterol (FC), and cholesteryl esters (CE) generally are notfreely circulating in plasma but instead are packaged togetherand transported through the body in larger lipoprotein particlesthat have amphipathic lipids and proteins as surface components.Low-density lipoprotein (LDL) and high-density lipoproteins(HDL) particles help move cholesterol to and from the periphery,respectively. The entire transport process is highly regulated interms of lipoprotein production and the transfer of lipids to andfrom these particles.CETP facilitates the transfer of CE from HDL containingapolipoprotein-A (apo-A) to apo-B-containing lipoproteins suchas very-low-density lipoprotein (VLDL) and LDL with abalanced exchange of TG. For every CE acquired from HDLand transferred to LDL or VLDL, CETP takes up one TGmolecule from LDL or VLDL and transfers it to HDL. Thus,CETP plays a critical role in both CE and TG transfer amonglipoproteins. A CETP inhibitor would thus be expected to raiseplasma HDL cholesterol (HDLc) levels, lower LDL cholesterol(LDLc), and provide a potential therapeutic benefit for patientswith coronary artery disease (CAD).As discussed in more detail below, whether CETP inhibitionmight induce an antiatherogenic response by raising HDLc orhave proatherogenic effects by interfering with reverse choles-terol transport (RCT) has been the subject of considerable debateand controversy.2-5Important insights from studies over thepast several years have added to our understanding of themultiple mechanisms by which HDL achieves its athero-protective effects6and the complex physiological and patho-physiological roles CETP plays in lipoprotein metabolism.However, the field still remains controversial. Recently, anumber of potent, selective, and orally active CETP inhibitorshave also been identified that raise HDLc in animals and moreclearly define the role of CETP in preclinical models ofatherosclerosis.2Several of these new CETP inhibitors havebeen brought forward and evaluated in clinical trials, and twohave now independently demonstrated phase II proof of conceptby dramatically increasing HDLc levels by 50% or more inhealthy volunteers and patients with low HDLc.7,8Thus, forthe first time, pharmacological agents are available that havethe potential to elevate HDLc in patients with low HDLc toabout the same extent that the current standard of care drugsreduce LDLc in hyperlipidemic patients. These exciting clinicalresults have generated renewed interest in CETP inhibition asa potential new therapeutic strategy for treating CAD, and morethan 750 related patents or publications have appeared inChemical Abstracts since 2000. It remains to be seen whetherprolonged treatment with these new agents leads to a profoundreduction in secondary coronary events across a broader patientpopulation without disrupting normal lipoprotein balance andfunction. This Perspective summarizes the current status oforally active CETP inhibitors as potential new treatments forCAD.Low HDLc as an Independent Risk Factor for CADAtherosclerosis describes the underlying progression inarterial dysfunction and remodeling that restricts blood flow tovessels in the peripheral vasculature and is ultimately manifestedas CAD. This remodeling is accompanied by the buildup of†Phone: (678)336-2733. Fax: (678)336-2501. E-mail: [email protected].© Copyright 2006 by the American Chemical SocietyVolume 49, Number 1 January 12, 200610.1021/jm058224l CCC: $33.50 © 2006 American Chemical SocietyPublished on Web 12/06/2005lipid-laden, cholesterol-rich fatty deposits within the vessel wallthat arise from the retention of modified LDL particles bymonocytes, macrophages, and T cells in the intimal space belowthe endothelial lining. The resulting atherosclerotic plaques arevulnerable to rupture and thrombus formation. The loss ofoxygen supply to the heart produces cellular and tissue injuryculminating in chest pain (angina), heart attack, and/or myo-cardial infarct (MI).9While smoking, hypertension, age, obesity, and family historyall contribute to CAD, dyslipidemia is one of the most prominentrisk factors for this disease. Epidemiological studies haveestablished correlations between various forms of dyslipidemiaand the accompanying risk of developing CAD. Hyperlipidemia,usually attributed to high levels of LDLc, is associated with asignificant risk for CAD. Nearly 60% of the circulatingcholesterol in human plasma is present as LDLc, and most ofthe higher overall total plasma cholesterol levels found in CADpatients is associated with LDLc. Historically, in healthy humansubjects total plasma cholesterol levels are believed to be inthe normal range when they occur below 200 mg/dL withaccompanying LDLc levels below 130 mg/dL and HDLc above40 mg/dL. In contrast, CAD patients have total plasmacholesterol concentrations of 250-300 mg/dL or more with acorresponding increased plasma LDLc.Compounds that target either cholesterol biosynthesis suchas the HMG-CoA reductase inhibitors10(statins) or agents thatlimit cholesterol absorption, e.g., ezetimibe,11significantlyreduced LDLc and lowered the incidence of coronary events inhyperlipidemic patients. In several prospective statin trials,lowering LDLc by 28-35% led to a corresponding 24-34%reduction in primary or secondary CAD mortality and morbidityin this patient population.12For every 1% lowering of LDLc,an approximate 1% reduction in CAD risk was observed.10,12As a result, statins have become first line therapy for loweringtotal plasma cholesterol levels. However, typically more than60% of the statin-treated patients in these controlled trialscontinued to develop cardiovascular disease and failed toexperience a therapeutic benefit.13Most of these nonrespondersalso had low HDLc levels.14Thus, there appears to be a largeunmet medical need for newer therapies that would provideadditional benefit to this sizable patient population that isnonresponsive to statins.In contrast, several


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