Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Curr Opin Lipidol. 2011 Aug;22(4):288-95. doi: 10.1097/MOL.0b013e3283475e00.
Review literature on the effect of decreasing cholesteryl ester transfer protein (CETP) activity through pharmacological inhibition or modulation in preclinical and clinical settings compared to human CETP deficiency on lipoprotein characteristics, HDL remodelling and function.
Torcetrapib, anacetrapib and dalcetrapib inhibited the heterotypic transfer of cholesteryl ester from HDL to LDL and/or VLDL with similar potency, although the potency of dalcetrapib was time dependent. Homotypic transfer of cholesteryl ester from HDL3 to HDL2 via recombinant human CETP was inhibited by torcetrapib and anacetrapib (CETP inhibitors, CETPi) but not by dalcetrapib (CETP modulator, CETPm). In a hamster model of reverse cholesterol transport, only dalcetrapib increased efflux of fecal sterols from macrophages to feces. In clinical studies, dose-responses of CETPi and CETPm demonstrate qualitative and quantitative changes in HDL and LDL particle composition and distribution.
Recent studies of the CETPi torcetrapib and anacetrapib and the CETPm dalcetrapib have shown differences in the resulting increase in HDL-cholesterol and in the level of HDL remodelling and potential for effective reverse cholesterol transport. Results from ongoing clinical outcomes studies with anacetrapib and dalcetrapib will clarify the relevance of CETP inhibition versus modulation towards HDL remodelling in the treatment of cardiovascular diseases.
比较临床前和临床环境中通过药理学抑制或调节降低胆固醇酯转移蛋白（CETP）活性与人类 CETP 缺乏对脂蛋白特征、HDL 重塑和功能的影响的文献。
Torcetrapib、anacetrapib 和 dalcetrapib 以相似的效力抑制 HDL 向 LDL 和/或 VLDL 的异质转移胆固醇酯，尽管 dalcetrapib 的效力是时间依赖性的。重组人 CETP 介导的 HDL3 向 HDL2 的同型转移胆固醇酯被 torcetrapib 和 anacetrapib（CETP 抑制剂，CETPi）抑制，但不受 dalcetrapib（CETP 调节剂，CETPm）抑制。在胆固醇逆向转运的仓鼠模型中，只有 dalcetrapib 增加了巨噬细胞内粪固醇向粪便的流出。在临床研究中，CETPi 和 CETPm 的剂量反应显示了 HDL 和 LDL 颗粒组成和分布的定性和定量变化。
最近对 CETPi torcetrapib 和 anacetrapib 以及 CETPm dalcetrapib 的研究表明，在增加 HDL-胆固醇的水平以及在 HDL 重塑和有效逆向胆固醇转运的潜力方面存在差异。正在进行的 anacetrapib 和 dalcetrapib 的临床结局研究的结果将阐明 CETP 抑制与调节对心血管疾病治疗中 HDL 重塑的相关性。
