A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits

Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for tr iglyceride in very low density lipoprotein (VLDL)(1,2). This process decrea ses the level of antiatherogenic HDL cholesterol and increases pro-atheroge nic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentia lly atherogenic(3-9). On the other hand, CETP could also be anti-atherogeni c(10-14), because it participates in reverse cholesterol transport (transfe r of cholesterol from peripheral cells through the plasma to the liver)(15) . Because the role of CETP in atherosclerosis remains unclear, we have atte mpted to develop a potent and specific CETP inhibitor. Here we describe CET P inhibitors that form a disulphide bond with CETP, and present one such in hibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholest erol and inhibits the progression of atherosclerosis in rabbits. Our findin gs indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential antiatherogenic drug.