Torcetrapib

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Torcetrapib
Torcetrapib.png
Names
IUPAC name
ethyl (2R,4S)-4-({[3,5-bis(trifluoromethyl)phenyl]methyl}(methoxycarbonyl)amino)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-1-carboxylate
Identifiers
262352-17-0 N
ChEBI CHEBI:49203 YesY
ChEMBL ChEMBL479527 YesY
ChemSpider 140123 YesY
Jmol 3D model Interactive image
KEGG D06195 YesY
PubChem 159325
UNII 4N4457MV2U YesY
  • 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 YesY
    Key: CMSGWTNRGKRWGS-NQIIRXRSSA-N YesY
  • 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
Vapor pressure {{{value}}}
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

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.

Medical uses

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

Mechanism

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 levels (the "good" cholesterol-containing particle) and reduces LDL levels (the "bad" cholesterol).[vague][citation needed]

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.[2]

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.[3]

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.[4]

Clinical trials

A 2004 trial (19 subjects, non-randomised) showed that torcetrapib could increase HDL and lower LDL with and without an added statin.[5]

Nine phase III studies were completed.[6][7][8][9][10][11][12][13][14][15]

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.[16] 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."[16] In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.[17] Pfizer recommended that all patients stop taking the drug immediately.[18]

Six studies were terminated early.[6] 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."[19]

The drug cost $800m+ to bring into Phase III development.[20]

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, “good” 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.

File:Torcetrapib synthesis.svg
Torcetrapib synthesis: U.S. Patent 6,313,142 Also see:[21][22]

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

References

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Notes

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 http://clinicaltrials.gov/ct2/results?term=torcetrapib
  7. ↑ http://clinicaltrials.gov/ct2/show/NCT00139061 Phase III Assess HDL-C Increase And Non-HDL Lowering Effect Of Torcetrapib/Atorvastatin Vs. Fenofibrate
  8. ↑ http://clinicaltrials.gov/ct2/show/NCT00134511 Phase III Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
  9. ↑ http://clinicaltrials.gov/ct2/show/NCT00134485 Phase III Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
  10. ↑ http://clinicaltrials.gov/ct2/show/NCT00134498 Phase III Study Comparing The Efficacy & Safety Of Torcetrapib/Atorvastatin And Atorvastatin In Subjects With High Triglycerides
  11. ↑ http://clinicaltrials.gov/ct2/show/NCT00267254 Phase III Clinical Trial Comparing Torcetrapib/Atorvastatin To Simvastatin In Subjects With High Cholesterol
  12. ↑ http://clinicaltrials.gov/ct2/show/NCT00138762 Phase III Study of Torcetrapib/Atorvastatin vs Atorvastatin Alone or Placebo in Patients With High Cholesterol
  13. ↑ http://clinicaltrials.gov/ct2/show/NCT00134173 Phase III Coronary IVUS Study to Compare Torcetrapib/Atorvastatin to Atorvastatin Alone in Subjects With Coronary Heart Disease (ILLUSTRATE)
  14. ↑ http://clinicaltrials.gov/ct2/show/NCT00137462 Phase III Lipitor Trial To Study The Effect Of Torcetrpib/Atorvastatin To Atorvastatin Alone.
  15. ↑ http://clinicaltrials.gov/ct2/show/NCT00136981 Phase III Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrapib/Atorvastatin to Atorvastatin Alone. (RADIANCE 1)
  16. ↑ 16.0 16.1 Lua error in package.lua at line 80: module 'strict' not found. (registration required)
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.[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)
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.[dead link] (Link dead as of 15 January 2007)
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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