The Pharmacology and Off-Target Effects of Some Cholesterol Ester Transfer Protein Inhibitors

https://doi.org/10.1016/j.amjcard.2009.09.017Get rights and content

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.

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Pharmacology of Cholesterol Ester Transfer Protein Inhibition

To date, 3 small molecule inhibitors of CETP have reached the clinical stage of development. For torcetrapib, the curtain fell in December 2006 after its use was shown to be associated with increased cardiovascular and noncardiovascular mortality in the large phase 3 end point trial Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE).17 Because there were important clues that torcetrapib possessed compound-related toxic effects unrelated to

Dalcetrapib

Dalcetrapib was the first small molecule CETP inhibitor to be developed. This thioester, S-(2-((1-(2-ethylbutyl)cyclohexane)carbonylamino)phenyl)2-methylpropanethioate (Figure 1) was shown to achieve 50% CETP inhibition in human plasma at a concentration of 9 μmmol/L (IC50). It binds to CETP through the formation of a covalent disulfide bond at its 13th amino acid residue (cysteine), inducing a conformational change in the protein. At a daily dose of 30 mg/kg, it inhibited rabbit CETP activity

Torcetrapib

Torcetrapib (4-[(3,5-Bis-trifluoromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; Figure 2) induces a nonproductive complex between CETP and HDL through a 5-fold reduction in the dissociation constant of CETP from HDL, thus blocking all of the major lipid transfer functions of CETP.33 The stronger binding to HDL increases CETP half-life, leading to 3–4 times the elevated levels of CETP in the circulation. The IC50 for

Anacetrapib

Anacetrapib ((4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-((2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl)methyl)-4-methyl-1,3-oxazolidin-2-one; MK-0859; Figure 3) shares structural and mechanistic properties with torcetrapib. Similar to torcetrapib, it induces a tight reversible bond between CETP and HDL, inhibiting CETP with a similar IC50 of 57 nmol/L. It competes for binding to CETP with both torcetrapib and dalcetrapib. In C57BL/6 mice transgenic for CETP,

Off-Target Effects of Cholesterol Ester Transfer Protein Inhibitors

Torcetrapib has consistently been associated with systolic blood pressure elevations of 3–6 mm Hg. Additionally, it lowers plasma potassium and increases sodium and bicarbonate levels with a concomitant increase in serum aldosterone levels.17, 24, 25, 26 It has been hypothesized that these changes somehow relate to the negative impact of torcetrapib on the cardiovascular event rate and total mortality. Indeed, the blood pressure changes caused by torcetrapib have been shown to be associated

Conclusion

Based on epidemiology and supported by a selection of genetic and preclinical evidence, CETP inhibitors were developed as a strategy to reduce the burden of atherosclerosis. Results with torcetrapib, the first compound to reach large-scale clinical development, were a grave disappointment, but the specific impact of CETP inhibition on cardiovascular risk may have been obscured by compound-specific, rather than class-specific adverse effects. Therefore, the final answer to the question of

Author Disclosures

The authors who contributed to this article have disclosed the following industry relationships.

Erik S.G. Stroes, MD, PhD, has received lecture fees from Roche Pharmaceuticals, Novartis Pharmaceuticals, and Merck & Co.

Menno Vergeer, MD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this article.

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      An increase in sodium and a decrease in both potassium and bicarbonate were observed with torcetrapib,26,32 which in combination with blood pressure increases suggested activation of the renin-angiotensin-aldosterone system. Further studies supported the concept of mineralocorticoid activation, demonstrating a greater prevalence of detectable aldosterone in torcetrapib-treated patients and administration up-regulation of release of aldosterone and cortisol by adrenocortical cells.33 Animal studies also revealed that torcetrapib administration was associated with increased aortic wall expression of endothelin, a potent vasoconstrictor.33

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