View source for Torcetrapib

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| ImageFile = Torcetrapib.svg
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| OtherNames =

| Section1 = {{Chembox Identifiers
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| UNII = 4N4457MV2U
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| PubChem = 159325
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  }}

| Section2 = {{Chembox Properties
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'''Torcetrapib''' (CP-529,414, [[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 clinical trials|phase III]] studies showed excessive all-cause mortality in the treatment group receiving a combination of [[atorvastatin]] (Lipitor) and torcetrapib.

==Medical uses==
Torcetrapib has not been found to reduce either [[cardiovascular disease]] or risk of death in those already taking a statin drug.<ref>{{cite journal|last1=Keene|first1=D|last2=Price|first2=C|last3=Shun-Shin|first3=MJ|last4=Francis|first4=DP|title=Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients|journal=BMJ (Clinical Research Ed.)|date=Jul 18, 2014|volume=349|pages=g4379|pmid=25038074|pmc=4103514|doi=10.1136/bmj.g4379}}</ref>

==Mechanism==
Torcetrapib acts (as a [[CETP inhibitor]]) 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 cholesterol levels and reduces LDL cholesterol levels. According to Harvard Heart Letter: "HDL cholesterol is turning out to be a much more complex substance than we once believed. Instead of a single kind of particle, HDL cholesterol is a family of different particles. Although they all contain lipids (fats), cholesterol, and proteins called apolipoproteins, some types are spherical while others are doughnut-shaped. Some types of HDL are great at plucking cholesterol from LDL and artery walls while other types are indifferent to cholesterol, and some even transfer cholesterol the wrong way — into LDL and cells"<ref>{{cite web |last1=Harvard Health Publishing |title=HDL: The good, but complex, cholesterol |date=March 2010 |url=https://www.health.harvard.edu/newsletter_article/hdl-the-good-but-complex-cholesterol}}</ref>

==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.<ref>{{cite web
 |last        = Buchwald
 |first       = Stephen
 |title       = Research Projects
 |url         = http://mit.edu/chemistry/buchwald/research/projects.html
 |date        = July 23, 2004
 |accessdate  = 2007-10-04
 |url-status     = dead
 |archive-url  = https://web.archive.org/web/20071025001047/http://mit.edu/chemistry/buchwald/research/projects.html
 |archive-date = 2007-10-25
}}</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 |url-status=dead |archive-url=https://web.archive.org/web/20061205085131/http://www.pfizer.com/pfizer/are/investors_releases/2005pr/mn_2005_0622.jsp |archive-date=2006-12-05 }}</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 = https://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 (19 subjects, non-randomised) showed that torcetrapib could increase HDL and lower LDL with and without an added statin.<ref>{{cite journal
 | last = Brousseau | first = ME 
 |author2=Schaefer EJ |author3=Wolfe ML |author4=Bloedon LT |author5=Digenio AG |author6=Clark RW |author7=Mancuso JP |author8=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 = 10.1056/NEJMoa031766| pmid = 15071125
 | doi-access = free }}</ref>

Nine phase III studies were completed.<ref name="bare_url">{{cite web|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/results?term=torcetrapib|title=Search results for torcetrapib}}</ref><ref>{{cite journal|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/show/NCT00139061|title=Phase III Assess HDL-C Increase And Non-HDL Lowering Effect Of Torcetrapib/Atorvastatin Vs. Fenofibrate|date=30 October 2007 }}</ref><ref>{{cite journal|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/show/NCT00134511|title=Phase III Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder|date=5 November 2007 }}</ref><ref>{{cite journal|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/show/NCT00134485|title=Phase III Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia|date=28 October 2007 }}</ref><ref>{{cite journal|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/show/NCT00134498|title=Phase III Study Comparing The Efficacy & Safety Of Torcetrapib/Atorvastatin And Atorvastatin In Subjects With High Triglycerides|date=15 November 2007 }}</ref><ref>{{cite journal|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/show/NCT00267254|title=Phase III Clinical Trial Comparing Torcetrapib/Atorvastatin To Simvastatin In Subjects With High Cholesterol|date=20 November 2007 }}</ref><ref>{{cite journal|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/show/NCT00138762|title=Phase III Study of Torcetrapib/Atorvastatin vs Atorvastatin Alone or Placebo in Patients With High Cholesterol|date=15 February 2012 }}</ref><ref>{{cite journal|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/show/NCT00134173|title=Phase III Coronary IVUS Study to Compare Torcetrapib/Atorvastatin to Atorvastatin Alone in Subjects With Coronary Heart Disease (ILLUSTRATE)|date=6 December 2007 }}</ref><ref>{{cite journal|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/show/NCT00137462|title=Phase III Lipitor Trial To Study The Effect Of Torcetrpib/Atorvastatin To Atorvastatin Alone|date=15 November 2007 }}</ref><ref>{{cite journal|publisher=U.S. National Library of Medicine|website=ClinicalTrials.gov|url=http://clinicaltrials.gov/ct2/show/NCT00136981|title=Phase III Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrapib/Atorvastatin to Atorvastatin Alone. (RADIANCE 1)|date=21 April 2015 }}</ref>

===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.<ref name="Berenson 20061203">{{cite news
 | first = Alex | last = Berenson 
 | title = Pfizer Ends Studies on Drug for Heart Disease
 | url = https://www.nytimes.com/2006/12/03/health/03pfizer.html?_r=1&th&emc=th&oref=slogin
 | work = [[The New York Times]]
 | date = December 3, 2006 | accessdate = 2006-12-03 |url-access=registration
}}</ref>
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."<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 |publisher=Associated Press | title = Pfizer ends cholesterol drug development
 | url = https://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_5&printer=1
 | via = Yahoo! News | date = December 3, 2006 | accessdate = 2006-12-03
}} {{Dead link|date=October 2010|bot=H3llBot}} ''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 recommended that all patients stop taking the drug immediately.<ref>{{cite news
 | agency = Associated Press
 | title = Pfizer cuts off cholesterol drug trials | url = https://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
}} {{Dead link|date=October 2010|bot=H3llBot}} (Link dead as of 15 January 2007)</ref>

Six studies were terminated early.<ref name="bare_url" /> 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."<ref>{{cite journal |title=Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial |date=July 2007 |author=Bots |doi=10.1016/S0140-6736(07)61088-5 |last2=Visseren |first2=Frank L |last3=Evans |first3=Gregory W |last4=Riley |first4=Ward A |last5=Revkin |first5=James H |last6=Tegeler |first6=Charles H |last7=Shear |first7=Charles L |last8=Duggan |first8=William T |last9=Vicari |first9=Ralph M |last10=Grobbee |first10=Diederick E |last11=Kastelein |first11=John J |journal=The Lancet |volume=370 |issue=9582 |pages=153–160 |display-authors=3 |pmid=17630038|s2cid=205949008 }}</ref>

The drug cost $800m+ to bring into Phase III development.<ref>{{cite journal
  | last = Cutler
  | first = D. M.
  | author-link = 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
  | doi = 10.1056/NEJMp078020
  | pmid = 17392299
  | issue = 13
  | issn = 1533-4406 }}</ref>

==Synthesis==
Dietary cholesterol needs be esterified in order to be absorbed from the gut. The enzyme, [[cholesterylester transfer protein]] (CETP), then completes the absorption of [[cholesterol]]. Drugs that interfere with the action of these peptides would aid in lowering cholesterol levels by complementing the action of the [[statins]] that inhibit the endogenous production of cholesterol. The CETP inhibitor torcetrapib ('''8''') proved very effective in lowering cholesterol levels in humans; the drug not only lowered low-density lipoproteins (LDL and VLDL) but also raised levels of high density lipoproteins ([[High-density lipoprotein|HDL]]). This agent, which had only a brief time on the market due to adverse safety reports, is included here to illustrate an unusual method for preparing tetrahydroquinolines.
[[File:Torcetrapib synthesis.svg|thumb|center|700px|Torcetrapib synthesis: {{US patent|6313142}} Also see:<ref>{{cite journal|doi=10.1021/op060014a|title=Synthesis of the CETP Inhibitor Torcetrapib: The Resolution Route and Origin of Stereoselectivity in the Iminium Ion Cyclization|journal=Organic Process Research & Development|volume=10|issue=3|pages=464|year=2006|last1=Damon|first1=David B.|last2=Dugger|first2=Robert W.|last3=Magnus-Aryitey|first3=George|last4=Ruggeri|first4=Roger B.|last5=Wester|first5=Ronald T.|last6=Tu|first6=Meihua|last7=Abramov|first7=Yuriy}}</ref><ref>{{cite journal|doi=10.1021/jo071031g|pmid=17625891|title=A Concise Asymmetric Synthesis of Torcetrapib|journal=The Journal of Organic Chemistry|volume=72|issue=16|pages=6290–3|year=2007|last1=Guinó|first1=Meritxell|last2=Phua|first2=Pim Huat|last3=Caille|first3=Jean-Claude|author-link4=Mimi Hii|last4=Hii|first4=King Kuok (Mimi)}}</ref>]]
Reaction of the trifluoromethylaniline ('''1''') with [[propanal]] in the presence of [[benzotriazole]] ('''2''') affords the aminal ('''3'''). Condensation of ('''3''') with the vinyl carbamate ('''4''') yields the [[tetrahydroquinoline]] ring ('''5''') with expulsion of the [[benzotriazole]] fragment. The ring nitrogen is then protected as its [[ethyl carbamate]] by acylation with [[ethyl chloroformate]] ('''6'''). The benzyl carbamate function on nitrogen at the 4 position is next removed by reduction with [[ammonium formate]] over [[palladium]] to afford the primary amine; this compound is then resolved as its dibenzyl tartrate salt to afford the 2R,4S isomer ('''7'''). Reductive amination with the bis-trifuoromethyl benzaldehyde in the presence of [[sodium triacetoxyborohydride]] followed by acylation with methyl chloroformate completes the synthesis of torcetrapib ('''8''').

==See also==
* [[CETP inhibitor]]
* [[Anacetrapib]], CETP inhibitor undergoing development by [[Merck & Co.|Merck]]
* [[Dalcetrapib]], CETP inhibitor which also failed in clinical trials

==References==

* {{cite journal
 | last = Clark | first = RW |author2=Sutfin TA |author3=Ruggeri RB |author4=Willauer AT |author5=Sugarman ED |author6=Magnus-Aryitey G |author7=Cosgrove PG |author8=Sand TM |author9=Wester RT |author10=Williams JA |author11=Perlman ME |author12=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 = 10.1161/01.ATV.0000118278.21719.17| pmid = 14739125 |doi-access=free }}

* {{cite journal
 |last         = Clark
 |first        = RW
 |author2      = Ruggeri RB
 |author3      = Cunningham D
 |author4      = Bamberger MJ
 |date         = March 2006
 |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          = 10.1194/jlr.M500349-JLR200
 |pmid         = 16326978
 |doi-access   = free
 }}

* {{cite journal
 |last=Davidson 
 |first=MH 
 |author2=McKenny JM 
 |author3=Shear CL 
 |author4=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=10.1016/j.jacc.2006.06.067 
 |pmid=17084249 
 |doi-access= 
 }}

* {{cite journal
 |last=McKenny 
 |first=JM 
 |author2=Davidson MH 
 |author3=Shear CL 
 |author4=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=10.1016/j.jacc.2006.06.066 
 |pmid=17084250 
 |doi-access=free 
 }}

===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:Carbamates]]
[[Category:Experimental monoclonal antibodies]]
[[Category:CETP inhibitors]]
[[Category:Trifluoromethyl compounds]]
[[Category:Drugs developed by Pfizer]]
[[Category:Quinolines]]
[[Category:Abandoned drugs]]