Torcetrapib

Last updated
Torcetrapib
Torcetrapib.svg
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
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.216.319 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • 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 Yes check.svgY
    Key: CMSGWTNRGKRWGS-NQIIRXRSSA-N Yes check.svgY
  • 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Contents

Medical uses

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

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

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

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

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: Torcetrapib synthesis.svg
Torcetrapib synthesis: U.S. Patent 6,313,142 Also see:

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

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle. HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Statin</span> Class of drugs used to lower cholesterol levels

Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most commonly prescribed cholesterol-lowering drugs.

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream. VLDL is assembled in the liver from triglycerides, cholesterol, and apolipoproteins. VLDL is converted in the bloodstream to low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL). VLDL particles have a diameter of 30–80 nm. VLDL transports endogenous products, whereas chylomicrons transport exogenous (dietary) products. In the early 2010s both the lipid composition and protein composition of this lipoprotein were characterised in great detail.

Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases (ASCVD), which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Apolipoprotein</span> Proteins that bind lipids to transport them in body fluids

Apolipoproteins are proteins that bind lipids to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.

Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Cholesteryl ester transfer protein</span> Mammalian protein found in Homo sapiens

Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.

A CETP inhibitor is a member of a class of drugs that inhibit cholesterylester transfer protein (CETP). They are intended to reduce the risk of atherosclerosis by improving blood lipid levels. At least three medications within this class have failed to demonstrate a beneficial effect.

<span class="mw-page-title-main">ApoA-I Milano</span>

Apolipoprotein A-I Milano is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease. ApoA-I Milano was first identified by Dr. Cesare Sirtori in Milan, who also demonstrated that its presence significantly reduced cardiovascular disease, even though it caused a reduction in HDL levels and an increase in triglyceride levels.

<span class="mw-page-title-main">Pitavastatin</span> Chemical compound

Pitavastatin is a member of the blood cholesterol lowering medication class of statins.

<span class="mw-page-title-main">Dalcetrapib</span> Chemical compound

Dalcetrapib is a CETP inhibitor which was being developed by Hoffmann–La Roche until May 2012. The drug was aimed at raising the blood levels of HDL cholesterol. Prevailing observations indicate that high HDL levels correlate with better overall cardiovascular health, though it remains unclear whether raising HDL levels consequently leads to an increase in cardiovascular health.

<span class="mw-page-title-main">Lomitapide</span> Chemical compound

Lomitapide, sold under the brand name Juxtapid in the US and Lojuxta in the EU, is a medication used as a lipid-lowering agent for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals. It has been tested in clinical trials as single treatment and in combinations with atorvastatin, ezetimibe and fenofibrate.

<span class="mw-page-title-main">Evacetrapib</span> Chemical compound

Evacetrapib was a drug under development by Eli Lilly & Company that inhibits cholesterylester transfer protein. CETP collects triglycerides from very low-density lipoproteins (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa, but primarily increasing high-density lipoprotein and lowering low-density lipoprotein. It is thought that modifying lipoprotein levels modifies the risk of cardiovascular disease. The first CETP inhibitor, torcetrapib, was unsuccessful because it increased levels of the hormone aldosterone and increased blood pressure, which led to excess cardiac events when it was studied. Evacetrapib does not have the same effect. When studied in a small clinical trial in people with elevated LDL and low HDL, significant improvements were noted in their lipid profile.

Esperion Therapeutics, Inc. is a public American pharmaceutical company focused on the development of bempedoic acid, an orally available small molecule designed to lower elevated levels of LDL-C. The company is headquartered in Ann Arbor, Michigan.

Inclisiran, sold under the brand name Leqvio, is a medication used for the treatment of high low-density lipoprotein (LDL) cholesterol and for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk-equivalents, and heterozygous familial hypercholesterolemia (HeFH). It is a small interfering RNA (siRNA) that acts as an inhibitor of a proprotein convertase, specifically, inhibiting translation of the protein PCSK9.

<span class="mw-page-title-main">Obicetrapib</span> Chemical compound

Obicetrapib is an experimental CETP inhibitor that is intended to treat dyslipidemia. In a clinical trial, as an add-on to statins, it decreased "LDL-C concentration, the primary trial outcome. As compared with placebo, obicetrapib treatment also significantly (P < 0.0001) decreased apolipoprotein B and non-high-density lipoprotein cholesterol (non-HDL-C) concentration, and significantly (P < 0.0001) increased HDL-C concentration ". As of 2023, it is in a Phase III trial.

References

Notes

  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). "Research Projects". Archived from the original on 2007-10-25. Retrieved 2007-10-04.
  4. ↑ "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.
  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. 1 2 "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. 1 2 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.
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