- Torcetrapib
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CASNo=262352-17-0
PubChem=159325
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Formula=C26H25F9N2O4
MolarMass=600.473
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Autoignition=Torcetrapib (CP-529414,
Pfizer ) was a drug being developed to treathypercholesterolemia (elevatedcholesterol levels) and preventcardiovascular disease . Its development was halted in 2006 when phase III studies showed excessive mortality in the treatment group receiving a combination of atorvastatin and the study drug.Mechanism
Torcetrapib acts by inhibiting
cholesterylester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density orlow density lipoprotein s (VLDL or LDL). Inhibition of this process results in higher HDL levels (the "good" cholesterol-containing particle) and reduces LDL levels (the "bad" cholesterol).Development
The first step in the synthesis was a recently created reaction of amination to p-chlorotriflouryltoluene, a reaction that was created by Dr. Stephen Buchwald at MIT. [cite website
last = Buchwald | first = Stephen | authorlink =
title = Research Projects
url = http://mit.edu/chemistry/buchwald/research/projects.html
date =July 23 2004 | accessdate = 2007-10-4]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. [cite press release | title = Pfizer Begins Production at Torcetrapib/Atorvastatin Manufacturing Facility | publisher = Pfizer | date =
June 22 2005 | url = http://www.pfizer.com/pfizer/are/investors_releases/2005pr/mn_2005_0622.jsp | accessdate = 2006-12-03 ]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. [cite news | first = Alex | last = Berenson | title = Heart Pill to Be Sold by Itself | url = http://www.nytimes.com/2006/07/26/business/26drug.html | work = Business | publisher = The New York Times | date =July 26 2006 | accessdate = 2006-12-03]Clinical trials
A 2004 trial showed that torcetrapib could increase HDL and lower LDL with and without an added statin. [cite journal
last = Brousseau | first = ME | authorlink =
coauthors = Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ
date =April 8 2004
title = Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol
journal =New England Journal of Medicine
volume = 350 | issue = 15 | pages = 1505–1515
doi = | pmid = 15071125
url = http://content.nejm.org/cgi/content/abstract/350/15/1505
accessdate = 2006-12-03
format = abstract ]End of study
On
December 2 2006 Pfizer cut off torcetrapib's trial because of "an imbalance of mortality and cardiovascular events" associated with its use.cite news
first = Alex | last = Berenson | authorlink =
title = Pfizer Ends Studies on Drug for Heart Diseas
url = http://www.nytimes.com/2006/12/03/health/03pfizer.html?_r=1&th&emc=th&oref=slogin
publisher =The New York Times
date =December 3 2006 | accessdate = 2006-12-03 (registration required)] This was a sudden and unexpected event and as recently as November 30Jeff Kindler , Pfizer’s chief executive, was quoted as saying "This will be one of the most important compounds of our generation." In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone. [cite news
author = Theresa Agovino (Associated Press) | title = Pfizer ends cholesterol drug development
url = http://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_5&printer=1
publisher = Yahoo! News | date =December 3 2006 | accessdate = 2006-12-03 "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 of15 January 2007 )] Pfizer recommends that all patients stop taking the drug immediately. [cite news
author = Associated Press
title = Pfizer cuts off cholesterol drug trials | url = http://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_1
work =Yahoo! News | publisher = Yahoo.com
date =December 2 2006 | accessdate = 2006-12-03 (Link dead as of15 January 2007 )]The drug cost $800m+ to bring into Phase III development. [cite journal
last = Cutler
first = D. M.
authorlink = D. M. Cutler
title = The Demise of the Blockbuster?
journal = The New England Journal of Medicine
volume = 356
pages = 1292–1293
date =2007-03-29
publisher = Massachusetts Medical Society
url = http://content.nejm.org/cgi/content/full/356/13/1292
format =HTML
id = ISSN: 1533-4406
accessdate = 2007-04-23
doi = 10.1056/NEJMp078020
pmid = 17392299 ]ee also
*
Anacetrapib , another CETP inhibitor currently studied by MerckReferences
* cite journal
last = Clark | first = RW | authorlink =
coauthors = Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ
date =January 22 2004
title = Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib
journal =Arteriosclerosis, Thrombosis, and Vascular Biology
volume = 24 | issue = 3 | pages = 490–497
doi = | pmid = 14739125 | url = http://atvb.ahajournals.org/cgi/content/full/24/3/490
accessdate = 2006-12-03* cite journal
last = Clark | first = RW | authorlink =
coauthors = Ruggeri RB, Cunningham D, Bamberger MJ
year = 2006 | month = March
title = Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action
journal =Journal of Lipid Research
volume = 47 | issue = 3 | pages = 537–552
doi = | pmid = 16326978 | url = http://www.jlr.org/cgi/content/full/47/3/537
accessdate = 2006-12-03* cite journal
last = Davidson | first = MH | authorlink = | coauthors = McKenny JM, Shear CL, Revkin JH
date =November 7 2006
title = Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels
journal =Journal of the American College of Cardiology | volume = 48 | issue = 9 | pages = 1774–1781
doi = | pmid = 17084249 | url = http://patient-research.elsevier.com/patientresearch/displayAbs?key=S0735109706019917
accessdate = 2006-12-03* cite journal
last = McKenny | first = JM | authorlink = | coauthors = Davidson MH, Shear CL, Revkin JH
date =November 7 2006
title = 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 = Journal of the American College of Cardiology
volume = 48 | issue = 9 | pages = 1782–1790
doi = | pmid = 17084250 | url = http://patient-research.elsevier.com/patientresearch/displayAbs?key=S0735109706019905
accessdate = 2006-12-03Notes
External links
* [http://www.medscape.com/viewarticle/548725_print Medscape / HEARTwire : Torcetrapib Torpedoed: Increased Risk of Mortality, Cardiovascular Events Ends Development.]
* [http://www.cholesteroldoc.com/cetp-inhibitors.htm#news latest news about CETP Inhibitors]
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