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Torcetrapib
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<h2 id="medical-uses">Medical uses</h2> <p>Torcetrapib has not been found to reduce either <a href="/facts/Cardiovascular_disease/HD420nMv">cardiovascular disease</a> or risk of death in those already taking a statin drug.<a class="footnote-ref" id="fnref:1" href="#fn:1"><sup>1</sup></a> </p> <h2 id="mechanism">Mechanism</h2> <p>Torcetrapib acts (as a <a href="/facts/CETP_inhibitor/VnY0hs84">CETP inhibitor</a>) by inhibiting <a href="/facts/Cholesterylester_transfer_protein/bGadPuxw">cholesterylester transfer protein</a> (CETP), which normally transfers cholesterol from <a href="/facts/High_density_lipoprotein/x7cs1ys9">HDL cholesterol</a> to <a href="/facts/Very_low_density_lipoprotein/uoQTgwX4">very low density</a> or <a href="/facts/Low_density_lipoprotein/R5VLPxAg">low density lipoproteins</a> (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"<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a> </p> <h2 id="development">Development</h2> <p>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.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p><p>Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer's <a href="/facts/Statin/ba4mes9W">statin</a>, <a href="/facts/Atorvastatin/2eJ0m0lz">atorvastatin</a> (Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetrapib to be sold independently of Lipitor.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> </p> <h2 id="clinical-trials">Clinical trials</h2> <p>A 2004 trial (19 subjects, non-randomised) showed that torcetrapib could increase HDL and lower LDL with and without an added statin.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p><p>Nine phase III studies were completed.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <h3>Early termination of study</h3> <p>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.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> This was a sudden and unexpected event and as late as November 30, 2006 <a href="/facts/Jeff_Kindler/M1d60flK">Jeff Kindler</a>, Pfizer's chief executive, was quoted, "This will be one of the most important compounds of our generation."<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> Pfizer recommended that all patients stop taking the drug immediately.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p><p>Six studies were terminated early.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> 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."<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p><p>The drug cost $800m+ to bring into Phase III development.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p> <h2 id="synthesis">Synthesis</h2> <p>Dietary cholesterol needs be esterified in order to be absorbed from the gut. The enzyme, <a href="/facts/Cholesterylester_transfer_protein/bGadPuxw">cholesterylester transfer protein</a> (CETP), then completes the absorption of <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a>. Drugs that interfere with the action of these peptides would aid in lowering cholesterol levels by complementing the action of the <a href="/facts/Statins/ba4mes9W">statins</a> 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 (<a href="/facts/High-density_lipoprotein/x7cs1ys9">HDL</a>). 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. </p> <p>Reaction of the trifluoromethylaniline (1) with <a href="/facts/Propanal/N6wpBbxx">propanal</a> in the presence of <a href="/facts/Benzotriazole/0rDlWNm5">benzotriazole</a> (2) affords the aminal (3). Condensation of (3) with the vinyl carbamate (4) yields the <a href="/facts/Tetrahydroquinoline/3Lpd6C0w">tetrahydroquinoline</a> ring (5) with expulsion of the <a href="/facts/Benzotriazole/0rDlWNm5">benzotriazole</a> fragment. The ring nitrogen is then protected as its <a href="/facts/Ethyl_carbamate/fINBPN4u">ethyl carbamate</a> by acylation with <a href="/facts/Ethyl_chloroformate/1BleLHtC">ethyl chloroformate</a> (6). The benzyl carbamate function on nitrogen at the 4 position is next removed by reduction with <a href="/facts/Ammonium_formate/kkGFRUUh">ammonium formate</a> over <a href="/facts/Palladium/AXMwDFxs">palladium</a> 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 <a href="/facts/Sodium_triacetoxyborohydride/endKhBtu">sodium triacetoxyborohydride</a> followed by acylation with methyl chloroformate completes the synthesis of torcetrapib (8). </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/CETP_inhibitor/VnY0hs84">CETP inhibitor</a></li> <li><a href="/facts/Anacetrapib/A5v6WrVD">Anacetrapib</a>, CETP inhibitor undergoing development by <a href="/facts/Merck_%26_Co./8YD8dvwR">Merck</a></li> <li><a href="/facts/Dalcetrapib/Yms9HmSm">Dalcetrapib</a>, CETP inhibitor which also failed in clinical trials</li></ul> <ul><li>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). <a href="https://doi.org/10.1161%2F01.ATV.0000118278.21719.17">"Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib"</a>. <i><a href="/facts/Arteriosclerosis,_Thrombosis,_and_Vascular_Biology/qtVPHIqM">Arteriosclerosis, Thrombosis, and Vascular Biology</a></i>. 24 (3): 490–497. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1161%2F01.ATV.0000118278.21719.17">10.1161/01.ATV.0000118278.21719.17</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14739125">14739125</a>.</li></ul> <ul><li>Clark, RW; Ruggeri RB; Cunningham D; Bamberger MJ (March 2006). <a href="https://doi.org/10.1194%2Fjlr.M500349-JLR200">"Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action"</a>. <i><a href="/facts/Journal_of_Lipid_Research/HUv8WLC7">Journal of Lipid Research</a></i>. 47 (3): 537–552. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1194%2Fjlr.M500349-JLR200">10.1194/jlr.M500349-JLR200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16326978">16326978</a>.</li></ul> <ul><li>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". <i><a href="/facts/Journal_of_the_American_College_of_Cardiology/lBeBV2ky">Journal of the American College of Cardiology</a></i>. 48 (9): 1774–1781. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.jacc.2006.06.067">10.1016/j.jacc.2006.06.067</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17084249">17084249</a>.</li></ul> <ul><li>McKenny, JM; Davidson MH; Shear CL; Revkin JH (November 7, 2006). <a href="https://doi.org/10.1016%2Fj.jacc.2006.06.066">"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"</a>. <i>Journal of the American College of Cardiology</i>. 48 (9): 1782–1790. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.jacc.2006.06.066">10.1016/j.jacc.2006.06.066</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17084250">17084250</a>.</li></ul> <h3>Notes</h3> <h2 id="external-links">External links</h2> <ul><li><a href="http://www.medscape.com/viewarticle/548725_print">Medscape / HEARTwire : Torcetrapib Torpedoed: Increased Risk of Mortality, Cardiovascular Events Ends Development.</a></li> <li><a href="http://www.cholesteroldoc.com/cetp-inhibitors.htm#news">latest news about CETP Inhibitors</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Keene, D; Price, C; Shun-Shin, MJ; Francis, DP (Jul 18, 2014). "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". BMJ (Clinical Research Ed.). 349: g4379. doi:10.1136/bmj.g4379. PMC 4103514. PMID 25038074. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103514" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103514</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Harvard Health Publishing (March 2010). "HDL: The good, but complex, cholesterol". <a href="https://www.health.harvard.edu/newsletter_article/hdl-the-good-but-complex-cholesterol" target="_blank">https://www.health.harvard.edu/newsletter_article/hdl-the-good-but-complex-cholesterol</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Buchwald, Stephen (July 23, 2004). "Research Projects". Archived from the original on 2007-10-25. Retrieved 2007-10-04. <a href="https://web.archive.org/web/20071025001047/http://mit.edu/chemistry/buchwald/research/projects.html" target="_blank">https://web.archive.org/web/20071025001047/http://mit.edu/chemistry/buchwald/research/projects.html</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>"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. <a href="https://web.archive.org/web/20061205085131/http://www.pfizer.com/pfizer/are/investors_releases/2005pr/mn_2005_0622.jsp" target="_blank">https://web.archive.org/web/20061205085131/http://www.pfizer.com/pfizer/are/investors_releases/2005pr/mn_2005_0622.jsp</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Berenson, Alex (July 26, 2006). "Heart Pill to Be Sold by Itself". Business. The New York Times. Retrieved 2006-12-03. <a href="https://www.nytimes.com/2006/07/26/business/26drug.html" target="_blank">https://www.nytimes.com/2006/07/26/business/26drug.html</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Brousseau, ME; Schaefer EJ; Wolfe ML; Bloedon LT; Digenio AG; Clark RW; Mancuso JP; Rader DJ (April 8, 2004). "Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol". New England Journal of Medicine. 350 (15): 1505–1515. doi:10.1056/NEJMoa031766. PMID 15071125. <a href="https://doi.org/10.1056%2FNEJMoa031766" target="_blank">https://doi.org/10.1056%2FNEJMoa031766</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>"Search results for torcetrapib". ClinicalTrials.gov. U.S. National Library of Medicine. <a href="https://clinicaltrials.gov/ct2/results?term=torcetrapib" target="_blank">https://clinicaltrials.gov/ct2/results?term=torcetrapib</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>"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. <a href="https://clinicaltrials.gov/ct2/show/NCT00139061" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00139061</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>"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. <a href="https://clinicaltrials.gov/ct2/show/NCT00134511" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00134511</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>"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. <a href="https://clinicaltrials.gov/ct2/show/NCT00134485" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00134485</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>"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. <a href="https://clinicaltrials.gov/ct2/show/NCT00134498" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00134498</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>"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. <a href="https://clinicaltrials.gov/ct2/show/NCT00267254" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00267254</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>"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. <a href="https://clinicaltrials.gov/ct2/show/NCT00138762" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00138762</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>"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. <a href="https://clinicaltrials.gov/ct2/show/NCT00134173" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00134173</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>"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. <a href="https://clinicaltrials.gov/ct2/show/NCT00137462" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00137462</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>"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 href="https://clinicaltrials.gov/ct2/show/NCT00136981" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00136981</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Berenson, Alex (December 3, 2006). "Pfizer Ends Studies on Drug for Heart Disease". The New York Times. Retrieved 2006-12-03. <a href="https://www.nytimes.com/2006/12/03/health/03pfizer.html?_r=1&th&emc=th&oref=slogin" target="_blank">https://www.nytimes.com/2006/12/03/health/03pfizer.html?_r=1&th&emc=th&oref=slogin</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Berenson, Alex (December 3, 2006). "Pfizer Ends Studies on Drug for Heart Disease". The New York Times. Retrieved 2006-12-03. <a href="https://www.nytimes.com/2006/12/03/health/03pfizer.html?_r=1&th&emc=th&oref=slogin" target="_blank">https://www.nytimes.com/2006/12/03/health/03pfizer.html?_r=1&th&emc=th&oref=slogin</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>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) <a href="https://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_5&printer=1" target="_blank">https://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_5&printer=1</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>"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) <a href="https://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_1" target="_blank">https://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_1</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>"Search results for torcetrapib". ClinicalTrials.gov. U.S. National Library of Medicine. <a href="https://clinicaltrials.gov/ct2/results?term=torcetrapib" target="_blank">https://clinicaltrials.gov/ct2/results?term=torcetrapib</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Bots; Visseren, Frank L; Evans, Gregory W; et al. (July 2007). "Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial". The Lancet. 370 (9582): 153–160. doi:10.1016/S0140-6736(07)61088-5. PMID 17630038. S2CID 205949008. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:22" class="footnote-back-ref">↩</a></p></li> <li id="fn:23"><p>Cutler, D. M. (2007-03-29). "The Demise of the Blockbuster?". The New England Journal of Medicine. 356 (13): 1292–1293. doi:10.1056/NEJMp078020. ISSN 1533-4406. PMID 17392299. <a href="/w/index.php?title=D._M._Cutler&action=edit&redlink=1" target="_blank">/w/index.php?title=D._M._Cutler&action=edit&redlink=1</a> <a href="#fnref:23" class="footnote-back-ref">↩</a></p></li> </ol>