Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action

Abstract

We have identified a series of potent cholesteryl ester transfer protein (CETP) inhibitors, one member of which, torcetrapib, is undergoing phase 3 clinical trials. In this report, we demonstrate that these inhibitors bind specifically to CETP with 1:1 stoichiometry and block both neutral lipid and phospholipid (PL) transfer activities. CETP preincubated with inhibitor subsequently bound both cholesteryl ester and PL normally; however, binding of triglyceride (TG) appeared partially reduced. Inhibition by torcetrapib could be reversed by titration with both native and synthetic lipid substrates, especially TG-rich substrates, and occurred to an equal extent after long or short preincubations. The reversal of TG transfer inhibition using substrates containing TG as the only neutral lipid was noncompetitive, suggesting that the effect on TG binding was indirect. Analysis of the CETP distribution in plasma demonstrated increased binding to HDL in the presence of inhibitor. Furthermore, the degree to which plasma CETP shifted from a free to an HDL-bound state was tightly correlated to the percentage inhibition of CE transfer activity. The finding by surface plasmon resonance that torcetrapib increases the affinity of CETP for HDL by z5-fold likely represents a shift to a binding state that is nonpermissive for lipid transfer. In summary, these data are consistent with a mechanism whereby this series of inhibitors block all of the major lipid transfer functions of plasma CETP by inducing a nonproductive complex between the transfer protein and HDL. Despite the demonstration of the atheroprotective effects of HDL over the past several decades (1-4), no current therapy exists that is effective and well tolerated for increasing the levels of this lipoprotein (5). Although the use of extended-release niacin (Niaspan) at daily doses of 2 g or less has served to minimize the high incidence of vasodilatory effects, such as flushing and itching (6), toleration issues continue to limit compliance. Also, at 2 g/day, niacin increases high density lipoprotein cholesterol (HDL-C) by ,30% (7). The high levels of HDL associated with human cholesteryl ester transfer protein (CETP) deficiency (8) have suggested CETP inhibition as a means of increasing HDL. Although expression of human CETP in transgenic mice has produced mixed results regarding its atherogenicity, more consistent antiatherogenic effects have resulted from the inhibition of endogenous CETP in rabbits (8). In the wake of the beneficial effects observed through CETP inhibition in rabbits by induction of autoantibodies (9) and by administration of a synthetic inhibitor (10), these interventions have progressed to trials aimed at increasing HDL in humans. Although the use of the CETP vaccine has yet to demonstrate sufficient anti-CETP response to increase HDL (11), 900 mg/day of the inhibitor JTT-705 increased HDL-C by 34% and decreased low density lipoprotein cholesterol (LDL-C) by 7% (12).We have identified a new series of CETP inhibitors culminating in the dev...

CETP inhibition in cardiovascular risk management: a critical appraisal

“…CETP contains several cysteine (Cys) residues of which Cys-13 is critically involved in its neutral sterol binding site [58]. Accordingly, JTT-705 does not inhibit transfer activity of a mutant CETP in which the cysteine 13 residue is replaced by serine [53], and CETP inhibitor action most likely involves the formation of a disulphide bond with Cys-13 of CETP [59]. Torcetrapib specifically binds to CETP with 1 : 1 stoichiometry and blocks the cholesteryl ester transfer-, as well as the triglyceride-and phospholipid transfer-promoting properties of CETP, but does not impair phosphatidylcholine transfer by PLTP [59].…”

Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk

“…Torcetrapib acts by increasing the affi nity of CETP for HDLs ( 63 ). This generates a tight complex that reduces the amount of CETP available to promote transfers of cholesteryl esters and triglycerides between different lipoprotein particles.…”

Potential Biological Activities, Molecular Docking and Synthesis of Novel Ag+, Ni +2 and Fe+3 Complexes with Schiff base N'-(1-(4-((3,4-dihydroquinolin-1(2H)-yl)sulfonyl) phenyl)ethylidene)-3-oxo-3H-benzo[f]chromene-2-carbohydrazide

“…Tetrahydroquinoline derivatives have widely pharmaceuticals applications [12][13][14][15][16][17] . The reactions of tetrahydroquinoline with different derivatives, which lead to modification of its medicinal purpose [18][19][20] . Sulfonamides are known to have a widely applications in several biological systems [21][22][23][24][25] .…”