Torcetrapib 262352-17-0

Mechanism

Torcetrapib acts by inhibiting cholesteryl ester 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).

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. 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. 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.

Clinical trials

A 2004 trial showed that torcetrapib could increase HDL and lower LDL with and without an added statin.

End of study

On December 2, 2006 Pfizer cut off torcetrapib's trial because of "an imbalance of mortality and cardiovascular events" associated with its use. This was a sudden and unexpected event and as recently as November 30 Jeff Kindler, Pfizer’s chief executive, was quoted as saying "This will be one of the most important compounds of our generation. "Pfizer recommends that all patients stop taking the drug immediately. The drug cost $800m+ to bring into Phase III development.