A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits

Hiroshi Okamoto (), Fumihiko Yonemori, Korekiyo Wakitani, Takashi Minowa, Kimiya Maeda and Hisashi Shinkai ()
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Hiroshi Okamoto: Biological/Pharmacological Research Laboratories
Fumihiko Yonemori: Biological/Pharmacological Research Laboratories
Korekiyo Wakitani: Biological/Pharmacological Research Laboratories
Takashi Minowa: Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, JT Inc.
Kimiya Maeda: Central Pharmaceutical Research Institute, JT Inc.
Hisashi Shinkai: Central Pharmaceutical Research Institute, JT Inc.

Nature, 2000, vol. 406, issue 6792, 203-207

Abstract: Abstract Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL)1,2. This process decreases the level of anti-atherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic3,4,5,6,7,8,9. On the other hand, CETP could also be anti-atherogenic10,11,12,13,14, because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver)15. Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.

Date: 2000
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DOI: 10.1038/35018119

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