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Torcetrapib

January 01, 1970

Torcetrapib (CP-529,414, Pfizer) was a 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 all-cause mortality in the treatment group receiving a combination of atorvastatin (Lipitor) and torcetrapib.

Torcetrapib
Names
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
  • 262352-17-0 N
3D model (JSmol)
  • Interactive image
ChEBI
  • CHEBI:49203 Y
ChEMBL
  • ChEMBL479527 Y
ChemSpider
  • 140123 Y
ECHA InfoCard 100.216.319
KEGG
  • D06195 Y
  • 159325
UNII
  • 4N4457MV2U Y
  • DTXSID20180873
  • InChI=1S/C26H25F9N2O4/c1-4-18-12-21(19-11-15(24(27,28)29)6-7-20(19)37(18)23(39)41-5-2)36(22(38)40-3)13-14-8-16(25(30,31)32)10-17(9-14)26(33,34)35/h6-11,18,21H,4-5,12-13H2,1-3H3/t18-,21+/m1/s1 Y
    Key: CMSGWTNRGKRWGS-NQIIRXRSSA-N Y
  • InChI=1/C26H25F9N2O4/c1-4-18-12-21(19-11-15(24(27,28)29)6-7-20(19)37(18)23(39)41-5-2)36(22(38)40-3)13-14-8-16(25(30,31)32)10-17(9-14)26(33,34)35/h6-11,18,21H,4-5,12-13H2,1-3H3/t18-,21+/m1/s1
    Key: CMSGWTNRGKRWGS-NQIIRXRSBY
  • FC(F)(F)c1cc(cc(c1)C(F)(F)F)CN(C(=O)OC)[C@@H]3c2c(ccc(c2)C(F)(F)F)N(C(=O)OCC)[C@@H](C3)CC
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).
N verify (what is YN ?)

Medical uses edit

Torcetrapib has not been found to reduce either cardiovascular disease or risk of death in those already taking a statin drug.[1]

Mechanism edit

Torcetrapib acts (as a CETP inhibitor) by inhibiting cholesterylester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (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"[2]

Development edit

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 edit

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 edit

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 edit

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 (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.

 
Torcetrapib synthesis: U.S. patent 6,313,142 Also see:[22][23]

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 edit

References edit

  • 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". Arteriosclerosis, Thrombosis, and Vascular Biology. 24 (3): 490–497. doi:10.1161/01.ATV.0000118278.21719.17. 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". Journal of Lipid Research. 47 (3): 537–552. doi:10.1194/jlr.M500349-JLR200. 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". Journal of the American College of Cardiology. 48 (9): 1774–1781. doi:10.1016/j.jacc.2006.06.067. 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. doi:10.1016/j.jacc.2006.06.066. PMID 17084250.

Notes edit

  1. ^ 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.
  2. ^ Harvard Health Publishing (March 2010). "HDL: The good, but complex, cholesterol".
  3. ^ Buchwald, Stephen (July 23, 2004). . Archived from the original on 2007-10-25. Retrieved 2007-10-04.
  4. ^ (Press release). Pfizer. June 22, 2005. Archived from the original on 2006-12-05. Retrieved 2006-12-03.
  5. ^ Berenson, Alex (July 26, 2006). "Heart Pill to Be Sold by Itself". Business. The New York Times. Retrieved 2006-12-03.
  6. ^ 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.
  7. ^ a b "Search results for torcetrapib". ClinicalTrials.gov. U.S. National Library of Medicine.
  8. ^ "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.
  9. ^ "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.
  10. ^ "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.
  11. ^ "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.
  12. ^ "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.
  13. ^ "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.
  14. ^ "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.
  15. ^ "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.
  16. ^ "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.
  17. ^ a b Berenson, Alex (December 3, 2006). "Pfizer Ends Studies on Drug for Heart Disease". The New York Times. Retrieved 2006-12-03.
  18. ^ 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)
  19. ^ "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)
  20. ^ 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.
  21. ^ 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.
  22. ^ Damon, David B.; Dugger, Robert W.; Magnus-Aryitey, George; Ruggeri, Roger B.; Wester, Ronald T.; Tu, Meihua; Abramov, Yuriy (2006). "Synthesis of the CETP Inhibitor Torcetrapib: The Resolution Route and Origin of Stereoselectivity in the Iminium Ion Cyclization". Organic Process Research & Development. 10 (3): 464. doi:10.1021/op060014a.
  23. ^ Guinó, Meritxell; Phua, Pim Huat; Caille, Jean-Claude; Hii, King Kuok (Mimi) (2007). "A Concise Asymmetric Synthesis of Torcetrapib". The Journal of Organic Chemistry. 72 (16): 6290–3. doi:10.1021/jo071031g. PMID 17625891.

External links edit

  • Medscape / HEARTwire : Torcetrapib Torpedoed: Increased Risk of Mortality, Cardiovascular Events Ends Development.
  • latest news about CETP Inhibitors

January 01, 1970
torcetrapib, pfizer, drug, being, developed, treat, hypercholesterolemia, elevated, cholesterol, levels, prevent, cardiovascular, disease, development, halted, 2006, when, phase, studies, showed, excessive, cause, mortality, treatment, group, receiving, combin. Torcetrapib CP 529 414 Pfizer was a 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 all cause mortality in the treatment group receiving a combination of atorvastatin Lipitor and torcetrapib Torcetrapib Names 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 CAS Number 262352 17 0 N 3D model JSmol Interactive image ChEBI CHEBI 49203 Y ChEMBL ChEMBL479527 Y ChemSpider 140123 Y ECHA InfoCard 100 216 319 KEGG D06195 Y PubChem CID 159325 UNII 4N4457MV2U Y CompTox Dashboard EPA DTXSID20180873 InChI InChI 1S C26H25F9N2O4 c1 4 18 12 21 19 11 15 24 27 28 29 6 7 20 19 37 18 23 39 41 5 2 36 22 38 40 3 13 14 8 16 25 30 31 32 10 17 9 14 26 33 34 35 h6 11 18 21H 4 5 12 13H2 1 3H3 t18 21 m1 s1 YKey CMSGWTNRGKRWGS NQIIRXRSSA N YInChI 1 C26H25F9N2O4 c1 4 18 12 21 19 11 15 24 27 28 29 6 7 20 19 37 18 23 39 41 5 2 36 22 38 40 3 13 14 8 16 25 30 31 32 10 17 9 14 26 33 34 35 h6 11 18 21H 4 5 12 13H2 1 3H3 t18 21 m1 s1Key CMSGWTNRGKRWGS NQIIRXRSBY SMILES FC F F c1cc cc c1 C F F F CN C O OC C H 3c2c ccc c2 C F F F N C O OCC C H C3 CC Properties Chemical formula 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 N verify what is Y N Infobox references Contents 1 Medical uses 2 Mechanism 3 Development 4 Clinical trials 4 1 Early termination of study 5 Synthesis 6 See also 7 References 7 1 Notes 8 External linksMedical uses editTorcetrapib has not been found to reduce either cardiovascular disease or risk of death in those already taking a statin drug 1 Mechanism editTorcetrapib acts as a CETP inhibitor by inhibiting cholesterylester transfer protein CETP which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins 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 2 Development editThe 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 editA 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 edit 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 editDietary 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 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 nbsp Torcetrapib synthesis U S patent 6 313 142 Also see 22 23 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 editCETP inhibitor Anacetrapib CETP inhibitor undergoing development by Merck Dalcetrapib CETP inhibitor which also failed in clinical trialsReferences editClark 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 Arteriosclerosis Thrombosis and Vascular Biology 24 3 490 497 doi 10 1161 01 ATV 0000118278 21719 17 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 Journal of Lipid Research 47 3 537 552 doi 10 1194 jlr M500349 JLR200 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 Journal of the American College of Cardiology 48 9 1774 1781 doi 10 1016 j jacc 2006 06 067 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 doi 10 1016 j jacc 2006 06 066 PMID 17084250 Notes edit 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 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 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 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 amp 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 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 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 Damon David B Dugger Robert W Magnus Aryitey George Ruggeri Roger B Wester Ronald T Tu Meihua Abramov Yuriy 2006 Synthesis of the CETP Inhibitor Torcetrapib The Resolution Route and Origin of Stereoselectivity in the Iminium Ion Cyclization Organic Process Research amp Development 10 3 464 doi 10 1021 op060014a Guino Meritxell Phua Pim Huat Caille Jean Claude Hii King Kuok Mimi 2007 A Concise Asymmetric Synthesis of Torcetrapib The Journal of Organic Chemistry 72 16 6290 3 doi 10 1021 jo071031g PMID 17625891 External links editMedscape HEARTwire Torcetrapib Torpedoed Increased Risk of Mortality Cardiovascular Events Ends Development latest news about CETP Inhibitors Retrieved from https en wikipedia org w index php title Torcetrapib amp oldid 1190950142, wikipedia, wiki, book, books, library,

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