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 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]
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. 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
- Dalcetrapib, CETP inhibitor which also failed in clinical trials
External links
References
- D Keene, C Price, MJ Shun-Shin, DP Francis. 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.), Jul 18, 2014^
- Harvard Health Publishing. HDL: The good, but complex, cholesterol March 2010^
- Stephen Buchwald. Research Projects