Torcetrapib
Names | |
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Preferred IUPAC name
Ethyl (2R,4S)-4-({[3,5-bis(trifluoromethyl)phenyl]methyl}(methoxycarbonyl)amino)-2-ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate | |
Identifiers | |
3D model (
JSmol ) |
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ChEBI | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard
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100.216.319 |
KEGG | |
PubChem CID
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UNII | |
CompTox Dashboard (EPA)
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Properties | |
C26H25F9N2O4 | |
Molar mass | 600.473 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Torcetrapib (CP-529,414,
Medical uses
Torcetrapib has not been found to reduce either cardiovascular disease or risk of death in those already taking a statin drug.[1]
Mechanism
Torcetrapib acts (as a
Development
The first step in the synthesis was a recently created reaction of amination to p-chlorotrifluoryltoluene, a reaction that was created by Dr. Stephen Buchwald at MIT.[3]
Development of the drug began around 1990; it was first administered in humans in 1999, and manufacturing at production scale began in Ireland in 2005.[4]
Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer's statin, atorvastatin (Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetrapib to be sold independently of Lipitor.[5]
Clinical trials
A 2004 trial (19 subjects, non-randomised) showed that torcetrapib could increase HDL and lower LDL with and without an added statin.[6]
Nine phase III studies were completed.[7][8][9][10][11][12][13][14][15][16]
Early termination of study
On December 2, 2006, Pfizer cut off torcetrapib's phase III trial because of "an imbalance of mortality and cardiovascular events" associated with its use.[17] This was a sudden and unexpected event and as late as November 30, 2006 Jeff Kindler, Pfizer's chief executive, was quoted, "This will be one of the most important compounds of our generation."[17] In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.[18] Pfizer recommended that all patients stop taking the drug immediately.[19]
Six studies were terminated early.[7] One of the completed studies found it raised systolic blood pressure and concluded "Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further."[20]
The drug cost $800m+ to bring into Phase III development.[21]
Synthesis
Dietary cholesterol needs be esterified in order to be absorbed from the gut. The enzyme,
Reaction of the trifluoromethylaniline (1) with
See also
- CETP inhibitor
- Anacetrapib, CETP inhibitor undergoing development by Merck
- Dalcetrapib, CETP inhibitor which also failed in clinical trials
References
- Clark, RW; Sutfin TA; Ruggeri RB; Willauer AT; Sugarman ED; Magnus-Aryitey G; Cosgrove PG; Sand TM; Wester RT; Williams JA; Perlman ME; Bamberger MJ (January 22, 2004). "Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib". PMID 14739125.
- Clark, RW; Ruggeri RB; Cunningham D; Bamberger MJ (March 2006). "Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action". PMID 16326978.
- Davidson, MH; McKenny JM; Shear CL; Revkin JH (November 7, 2006). "Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels". PMID 17084249.
- McKenny, JM; Davidson MH; Shear CL; Revkin JH (November 7, 2006). "Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin". Journal of the American College of Cardiology. 48 (9): 1782–1790. PMID 17084250.
Notes
- PMID 25038074.
- ^ Harvard Health Publishing (March 2010). "HDL: The good, but complex, cholesterol".
- ^ Buchwald, Stephen (July 23, 2004). "Research Projects". Archived from the original on 2007-10-25. Retrieved 2007-10-04.
- ^ "Pfizer Begins Production at Torcetrapib/Atorvastatin Manufacturing Facility" (Press release). Pfizer. June 22, 2005. Archived from the original on 2006-12-05. Retrieved 2006-12-03.
- ^ Berenson, Alex (July 26, 2006). "Heart Pill to Be Sold by Itself". Business. The New York Times. Retrieved 2006-12-03.
- PMID 15071125.
- ^ a b "Search results for torcetrapib". ClinicalTrials.gov. U.S. National Library of Medicine.
- ^ "Phase III Assess HDL-C Increase And Non-HDL Lowering Effect Of Torcetrapib/Atorvastatin Vs. Fenofibrate". ClinicalTrials.gov. U.S. National Library of Medicine. 30 October 2007.
- ^ "Phase III Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder". ClinicalTrials.gov. U.S. National Library of Medicine. 5 November 2007.
- ^ "Phase III Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia". ClinicalTrials.gov. U.S. National Library of Medicine. 28 October 2007.
- ^ "Phase III Study Comparing The Efficacy & Safety Of Torcetrapib/Atorvastatin And Atorvastatin In Subjects With High Triglycerides". ClinicalTrials.gov. U.S. National Library of Medicine. 15 November 2007.
- ^ "Phase III Clinical Trial Comparing Torcetrapib/Atorvastatin To Simvastatin In Subjects With High Cholesterol". ClinicalTrials.gov. U.S. National Library of Medicine. 20 November 2007.
- ^ "Phase III Study of Torcetrapib/Atorvastatin vs Atorvastatin Alone or Placebo in Patients With High Cholesterol". ClinicalTrials.gov. U.S. National Library of Medicine. 15 February 2012.
- ^ "Phase III Coronary IVUS Study to Compare Torcetrapib/Atorvastatin to Atorvastatin Alone in Subjects With Coronary Heart Disease (ILLUSTRATE)". ClinicalTrials.gov. U.S. National Library of Medicine. 6 December 2007.
- ^ "Phase III Lipitor Trial To Study The Effect Of Torcetrpib/Atorvastatin To Atorvastatin Alone". ClinicalTrials.gov. U.S. National Library of Medicine. 15 November 2007.
- ^ "Phase III Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrapib/Atorvastatin to Atorvastatin Alone. (RADIANCE 1)". ClinicalTrials.gov. U.S. National Library of Medicine. 21 April 2015.
- ^ a b Berenson, Alex (December 3, 2006). "Pfizer Ends Studies on Drug for Heart Disease". The New York Times. Retrieved 2006-12-03.
- ^ Theresa Agovino (December 3, 2006). "Pfizer ends cholesterol drug development". Associated Press. Retrieved 2006-12-03 – via Yahoo! News. [dead link] Each study arm (torcetrapib + atorvastatin vs. atorvastatin alone) had 7500 patients enrolled; 51 deaths were observed in the atorvastatin alone arm, while 82 deaths occurred in the torcetrapib + atorvastatin arm. (Link dead as of 15 January 2007)
- ^ "Pfizer cuts off cholesterol drug trials". Yahoo! News. Yahoo.com. Associated Press. December 2, 2006. Retrieved 2006-12-03. [dead link] (Link dead as of 15 January 2007)
- S2CID 205949008.
- PMID 17392299.
- .
- PMID 17625891.