Torcetrapib (CP-529414) is an inhibitor of cholesteryl ester transfer protein (CETP), it may reduce atherosclerotic vascular disease by increasing levels of high-density lipoprotein (HDL) cholesterol. In vivo endothelial mediated vasodilation was assessed using ultrasound imaging of acetylcholine-induced changes in rabbit central ear artery diameter. Torcetrapib, in addition to producing hypertension and baseline vasoconstriction, markedly inhibited acetylcholine-induced vasodilation. A structurally distinct CETP inhibitor, JNJ-28545595, did not affect endothelial function despite producing similar degrees of CETP inhibition and high-density lipoprotein elevation. Nitroprusside normalized torcetrapib's basal vasoconstriction and elicited dose-dependent vasodilation of norepinephrine preconstricted arteries in torcetrapib-treated animals, indicating torcetrapib did not impair smooth muscle function.
|Cell lines||human adrenal carcinoma H295R cells|
|Preparation method||To test our hypothesis that torcetrapib acts directly on the adrenal gland to increase adrenal steroid production and consequently causes electrolyte imbalance in the ILLUMINATE trial, human adrenal carcinoma H295R cells were incubated with torcetrapib for 24 and 48 h. Aldosterone and cortisol concentrations in the media were monitored by RIA and LC-MS-MS, respectively. Angiotensin II was used as a positive control. As shown in Fig. 1A, torcetrapib dose-dependently increased aldosterone release from H295R cells after either 24 or 48 h of treatment with an EC50 of approximately 80 nM.|
|Concentrations||10, 30, 100, 300, 1000 and 3000 n M|
|Incubation time||24 and 48 h|
|Animal models||Male New Zealand White rabbits|
|Formulation||0.2% cholesterol, 10% coconut oil, and 1.2% ethyl lactate|
|Dosages||0.15, 0.3, and 0.6% (w/w) 1 week ∼90 mg/kg/day|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥5 mg/mL|
Relationship between atorvastatin dose and the harm caused by torcetrapib.
Barter et al. J Lipid Res. 2012 Sep 2. PMID: 22941786.
On- and off-target pharmacology of torcetrapib: current understanding and implications for the structure activity relationships (SAR), discovery and development of cholesteryl ester-transfer protein (CETP) inhibitors.
Johns et al. Drugs. 2012 Mar 5;72(4):491-507. PMID: 22356288.
Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition.
Hu X, et al. Endocrinology. 2009 May;150(5):2211-9. PMID: 19164467.
Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits.
Morehouse LA, et al. J Lipid Res. 2007 Jun;48(6):1263-72. PMID: 17325387.
|Related CETP Products|
Dalcetrapib (JTT-705) is a rhCETP inhibitor with IC50 of 0.2 μM that increases the plasma HDL cholesterol.
Evacetrapib (LY2484595) is a potent and selective inhibitor of CETP which inhibited human recombinant CETP protein (5.5 nM IC(50)) and CETP activity in human plasma (36 nM IC(50)) in vitro.
Anacetrapib is an orally active and potent inhibitor of CETP with IC50 of 7.9 nM and 11.8 nM for rhCETP and mutant CETP(C13S) respectively.
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