Disease relevance of CP-529414

• Effect of torcetrapib on the progression of coronary atherosclerosis [1].
• Experimental drug can double levels of "good" cholesterol. But does torcetrapib cut the risk of heart disease [2]?
• Will torcetrapib be the next big thing in coronary heart disease risk reduction [3].
• A secondary measure, the change in normalized atheroma volume, showed a small favorable effect for torcetrapib (P=0.02), but there was no significant difference in the change in atheroma volume for the most diseased vessel segment [1].
• METHODS AND RESULTS: Nineteen subjects, 9 of whom were taking 20 mg of atorvastatin for hypercholesterolemia, received placebo for 4 weeks, followed by the CETP inhibitor torcetrapib (120 mg QD) for 4 weeks [4].

High impact information on CP-529414

• Because these naturally occurring variant proteins are potentially present in clinical populations that will be treated with CETP inhibitors, all commonly occurring haplotypes were tested to determine whether the proteins they encode could be inhibited by torcetrapib, a compound currently in clinical trials in combination with atorvastatin [5].
• The finding by surface plasmon resonance that torcetrapib increases the affinity of CETP for HDL by approximately 5-fold likely represents a shift to a binding state that is nonpermissive for lipid transfer [6].
• In addition, other drugs, such as ezetimibe, colesevelam, torcetrapib, avasimibe, implitapide, and niacin are also being considered to manage hyperlipidemia [7].
• The effectiveness of these drugs on (intermediate) clinical outcome measures is currently being tested in large-scale phase III clinical trials, with torcetrapib being only evaluated in combination therapy with atorvastatin [8].
• 0. Torcetrapib was also associated with an increase in systolic blood pressure of 4.6 mm Hg [1].

Biological context of CP-529414

• When the dosage of torcetrapib was doubled (at maximum tolerated dose), HDL increased by over 100% [9].
• Proof that this may reduce atherosclerotic vascular disease is provided by population studies of cholesteryl ester transfer protein (CETP) deficiencies and single nucleotide polymorphisms of CETP, and experiments in animal models treated with torcetrapib [3].

Anatomical context of CP-529414

• OBJECTIVE: To determine whether cholesteryl ester transfer protein (CETP) directly mediates selective uptake of high-density lipoprotein (HDL)-cholesteryl ester (CE) by hepatocytes and to quantify the effects of the CETP inhibitor, torcetrapib, on this process [10].

Associations of CP-529414 with other chemical compounds

• Finally, torcetrapib significantly altered the distribution of cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort [11].

Gene context of CP-529414

• A new CETP inhibitor, Torcetrapib, was tested in humans and there was a 50-100% increase in HDL-C [12].
• Relative to placebo, 120 mg daily torcetrapib increased the amount of apoA-I in alpha1-migrating HDL in the atorvastatin (136%; P<0.001) and nonatorvastatin (153%; P<0.01) cohorts, whereas an increase of 382% (P<0.01) was observed in the 120 mg twice daily group [4].

Analytical, diagnostic and therapeutic context of CP-529414

• We have identified a series of potent cholesteryl ester transfer protein (CETP) inhibitors, one member of which, torcetrapib, is undergoing phase 3 clinical trials [6].
• The plasma samples were incubated with Torcetrapib at 37 degrees C, and the incubation was stopped with the addition of sodium bromide and cooling to 4 degrees C. The plasma samples were then separated by density gradient ultracentrifugation to their lipoprotein fractions [13].
• After treatment with atorvastatin to reduce levels of low-density lipoprotein (LDL) cholesterol to less than 100 mg per deciliter (2.59 mmol per liter), patients were randomly assigned to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily [1].

References