Torcetrapib - CAS 262352-17-0
Catalog number: 262352-17-0
Category: Inhibitor
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Torcetrapib is a Cholesteryl ester transfer protein (CETP) inhibitor. CETP normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels (the "good" cholesterol-containing particle) and reduces LDL levels (the "bad" cholesterol). Unfortunately clinical trials were stopped because of excessive all cause mortality. Reasons are still being investigated, but may be related to some off target effects such as an increase in aldosterone secretion not found in some other CETP inhibitors.
CP-529414; CP 529414; CP529414
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1. Will Torcetrapib Be the Next Big Thing in Coronary Heart Disease Risk Reduction?
James M. McKenney, John A. Hoekstra. Current Atherosclerosis Reports 2007, 9:48–56
Single nucleotide polymorphisms in human CETP have also been used to study the impact of a less active CETP molecule on CHD risk. One such evaluation was completed of the TaqIB variant of CETP among 13,677 patients. Those who had a B2B2 genotype had lower CETP levels, 10% higher HDL-C levels, and 22% fewer CHD events compared with B1B1 genotype patients [39]. The study of other CETP polymorphaisms does not find as clear a signal of benefit. Recently, a small study found no increase in fecal sterol in subjects administered torcetrapib. This could be interpreted to mean that torcetrapib does not increase delivery of CE to the liver via RCT. However, in CETP-deficient patients, investigators have found that cholesterol efflux from macrophages is enhanced through the transport of cholesterol with ABCG-1 to mature HDL particles and through an increase in apoE-HDL particles, which have a greater capacity to store CE in their core [26••]. These observational studies generally support the potential benefit of CETP inhibition.
2. Use of bile correction factors for allometricprediction of human pharmacokinetic parameters of torcetrapib, a facile cholesteryl ester transfer protein inhibitor
The recentdevelopmentsattributing to an increased mortality when torcetrapib was added to atorvastatin in the ILLUMINATE trial (the active arm) has led to the discontinuationoftorcetrapib from clinical development. While theunderlyingreason(s) for this phenomenonis still largely unknown,recent clinical safety data publishedfrom anacetrapib, another potent CETP inhibitor, suggested that blood pressure elevation producedby torcetrapib may be related tooff-targeteffect due to the natureofchemical structure oftorcetrapib and/or its metabolite(s) thereof, as opposed to the CETP target inhibition. Therefore, although CETP class of compounds is yet to be approved, emerging efficacyand pharmacodynamic data from anacetrapib has confirmedthe promiseofthis new class ofcompounds.
3. Thein VitroPlasma Distribution of a Novel Cholesteryl Ester Transfer Protein Inhibitor, Torcetrapib, Is Influenced by Differences in Plasma Lipid Concentrations
S. D. Lee, K. M. Wasan, A. Calcagni, M. Avery, F. McCush, and C. Chen. Pharmaceutical Research, Vol. 23, No. 5, May 2006
Recently, a new CETP inhibitor, Torcetrapib (CP-529,414), was developed and tested in two studies in human subjects. In the first, the effect of CETP inhibition on plasma HDL levels was studied in healthy subjects (13). With the highest dose of 120 mg administered orally twice daily for 14 days, CETP activity decreased by 80%, although the CETP mass increased, apparently because the mechanism of action of Torcetrapib represents the shift of free CETP to HDL-bound form. With the above treatment, plasma LDL decreased by 42% and HDL cholesterol (HDL-C) increased by 91%, as did apo Al and apo E, by 27 and 66%, respectively. In the second study, Torcetrapib was given to 19 normal subjects with low plasma HDL-C levels (<40 mg/dL), nine of whom received 20 mg atorvastatin daily. In subjects who received only 120 mg/day Torcetrapib for 4 weeks, HDL was increased by 46%; in those treated also with atorvastatin, the increase was 61%. A much higher rise in HDL-C, 106%, was observed when the drug was given twice daily, but with no atorvastatin. In six subjects treated with the two drugs, there was also a 17% decrease in LDL cholesterol (LDL-C). In addition, Torcetrapib decreased the levels of the proatherogenic small dense LDL particles and increased the concentration of large HDL to values seen in subjects with normolipidemia. However, to date, limited information about the plasma distribution of Torcetrapib following administration has been reported.
4. API Quality by Design Example from the Torcetrapib Manufacturing Process
Dave am Ende & Karen S. Bronk & Jason Mustakis. J Pharm Innov (2007) 2:71–86
The first step to define the design space for the manufacturing process of torcetrapib API was to identify CQAs. Obvious CQAs are defined as a drug substance characteristic that has a direct or indirect impact on the safety and efficacy of the drug product (for example, the impurity profile of the drug substance). While several QAs were controlled by the torcetrapib API specifications, the only ones that were considered critical were assay and impurity limits. The other specification criteria, i.e., identity, appearance, physical characteristics, etc., were important for ensuring appropriate material attributes for subsequent drug product manufactur-ability but did not demonstrate a risk to safety and efficacy. Therefore, development of design space for the torcetrapib API manufacturing process was oriented toward establishing boundaries for control of impurities, which were the primary focus for the experimental designs. Limits for impurity levels in the API provide the basis for ultimate demonstration of control. However, the limits may be achieved by purge during the synthesis provided the combination of conditions is favorably disposed to consistently reduce or eliminate them. Therefore, specified testing limits in the API specification for those impurities may be rendered superfluous. QAs of synthetic intermediates are not necessarily critical.
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