Torcetrapib 3184009 221316949 2008-06-24T00:14:53Z DOI bot 6652755 Citation maintenance. Initiated by [[User:Fconaway|Fconaway]]. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{Chembox new |ImageFile=Torcetrapib.png |ImageSize= |IUPACName= |OtherNames= |Section1= {{Chembox Identifiers | CASNo=262352-17-0 | PubChem=159325 | SMILES= }} |Section2= {{Chembox Properties | Formula=C<sub>26</sub>H<sub>25</sub>F<sub>9</sub>N<sub>2</sub>O<sub>4</sub> | MolarMass=600.473 | Appearance= | Density= | MeltingPt= | BoilingPt= | Solubility= }} |Section3= {{Chembox Hazards | MainHazards= | FlashPt= | Autoignition= }} }} '''Torcetrapib''' (CP-529414, [[Pfizer]]) was a [[medication|drug]] being developed to treat [[hypercholesterolemia]] (elevated [[cholesterol]] levels) and prevent [[cardiovascular 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 [[High density lipoprotein|HDL cholesterol]] to [[Very low density lipoprotein|very low density]] or [[low 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.<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> 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.<ref>{{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}}</ref> ==Clinical trials== A 2004 trial showed that torcetrapib could increase HDL and lower LDL with and without an added statin.<ref>{{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&ndash;1515 | doi = | pmid = 15071125 | url = http://content.nejm.org/cgi/content/abstract/350/15/1505 | accessdate = 2006-12-03 | format = abstract }}</ref> ==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.<ref name="Berenson 20061203">{{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)</ref> This was a sudden and unexpected event and as recently as November 30 [[Jeff Kindler]], Pfizer’s chief executive, was quoted as saying "''This will be one of the most important compounds of our generation.''"<ref name="Berenson 20061203"/> In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.<ref>{{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 of [[15 January]] [[2007]])</ref> Pfizer recommends that all patients stop taking the drug immediately.<ref>{{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 of [[15 January]] [[2007]])</ref> The drug cost $800m+ to bring into Phase III development.<ref>{{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 }}</ref> ==See also== *[[Anacetrapib]], another CETP inhibitor currently studied by [[Merck & Co.|Merck]] ==References== * {{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&ndash;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&ndash;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&ndash;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&ndash;1790 | doi = | pmid = 17084250 | url = http://patient-research.elsevier.com/patientresearch/displayAbs?key=S0735109706019905 | accessdate = 2006-12-03 }} ===Notes=== <References/> ==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] {{Lipid modifying agents}} [[Category:Hypolipidemic agents]] [[pl:Torcetrapib]]