生物活性

• 描述Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to very low-density lipoprotein and low-density lipoprotein (LDL). Therefore, CETP inhibition raises high-density lipoprotein cholesterol (HDL-C) levels and decreases LDL-C levels^[7]. Dalcetrapib is a CETP inhibitor with IC₅₀ of 0.2 μM that increases the plasma HDL cholesterol^[8]. Dalcetrapib induces a conformational change in CETP, when added to human plasma. CETP-induced pre-β-HDL formation in human plasma is unchanged by dalcetrapib ≤3 μM and increased at 10 μM. Dalcetrapib statistically and significantly increases pre-β-HDL formation^[8]. Dalcetrapib achieves 50% inhibition of CETP activity in human plasma at a concentration of 9 μM^[9]. Dalcetrapib inhibits the CETP activity of media in HepG2 in a dose-dependent manner^[10]. Treatment with Dalcetrapib leads to significant increases in HDL-C levels. In hamsters injected with [³H]cholesterol-labeled autologous macrophages. dalcetrapib significantly increases fecal elimination of both [³H]neutral sterols and [³H]bile acids. Dalcetrapib increases plasma HDL-[³H]cholesterol^[8]. Dalcetrapib increases the plasma HDL cholesterol level by 27% and 54%, respectively, when given at oral doses of 30 mg/kg or 100 mg/kg once a day for 3 days to male Japanese white rabbits^[9].

• 动物研究
  剂量	Rat: 100 mg/kg[3] (p.o.); 10 mg/kg[3] (i.v.) Monkey: 100 mg/kg[3] (p.o.); 10 mg/kg[3] (i.v.) Hamsters: 200 mg/kg[4] (p.o., BID) Rabbit: 10 mg/kg - 100 mg/kg[5] (p.o.) Male cynomolgus monkey: 50 mg/kg[6] (p.o.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Rats[3] Monkeys[3] Dose 10 mg/kg (i.v.) 100 mg/kg (p.o.) 10 mg/kg (i.v.) 100 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. F 26.9 ± 7.0% (p.o.) 18.0% (p.o.) Tmax 1.7 ± 0.6 h (p.o.) 4 h (p.o.) tt1/2β 12.5 h (i.v.) 8.4 h (p.o.) AUCinf 19.41 μg·Eq·h/ml (i.v.) 35.03 μg·Eq·h/ml (p.o.) AUC0-inf 6.75 ± 1.09 μg·Eq·h/ml (i.v.) 18.16 ± 4.71 μg·Eq·h/ml (p.o.) C0 14.17 ± 4.99 μg Eq/ml (i.v.) 7.94 μg Eq/ml (i.v.) Vss 5.18 ± 0.97 L/kg (i.v.) 6.25 L/kg (i.v.) T1/2β 5.5 ± 1.3 h (i.v.) 4.0 ± 0.3 h (p.o.) Cmax 2.80 ± 0.75 μg Eq/ml (p.o.) 2.16 μg Eq/ml (p.o.) CL 1.51 ± 0.26 L/h/kg (i.v.) 0.52 L/h/kg (i.v.) T1/2α 0.15 ± 0.09 h (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00655538	Coronary Heart Disease	Phase 2	Completed	-	Austria ... more >> Feldkirch, Austria, 6800 France Paris, France, 75908 Germany Bonn, Germany, 53127 Dortmund, Germany, 44137 Frankfurt, Germany, 60596 Mainz, Germany, 55131 Wuppertal, Germany, 42117 Italy Pisa, Toscana, Italy, 56100 Netherlands Amsterdam, Netherlands, 1105 AZ Breda, Netherlands, 4811 SW Eindhoven, Netherlands, 5611 NJ Goes, Netherlands, 4462 RA Groningen, Netherlands, 9711 SG Hoorn, Netherlands, 1625 HV Leiderdorp, Netherlands, 2352 RA Nijmegen, Netherlands, 6525 EC Rotterdam, Netherlands, 3021 HC Utrecht, Netherlands, 3508 GA Velp, Netherlands, 6883 ES Zoetermeer, Netherlands, 2724 EK Switzerland Lugano, Switzerland, 6900 Zürich, Switzerland, 8091 United Kingdom Cardiff, United Kingdom, CF14 4XN Collapse <<
  NCT00658515	Coronary Heart Disease	Phase 3	Completed	-	-
  NCT00686010	Type II Hyperlipidaemia	Phase 2	Completed	-	Netherlands ... more >> Amsterdam, Utrecht, Rotterdam, Nijmegen, Arnhem, Groningen, Dordrecht, Hoorn, Groningen Amsterdam, Netherlands Collapse <<

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• 参考文献

• [1] Niesor EJ, Magg C, et al. Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport. J Lipid Res. 2010 Dec;51(12):3443-54.

  [2] Shinkai H, Maeda K, et al. bis(2-(Acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, and S-(2-(acylamino)phenyl) alkanethioates as novel inhibitors of cholesteryl ester transfer protein. J Med Chem. 2000 Sep 21;43(19):3566-72.

  [3] Takubo H, Ishikawa T, et al. Pharmacokinetics and disposition of dalcetrapib in rats and monkeys. Xenobiotica. 2014 Dec;44(12):1117-26.

  [4] Briand F, Thieblemont Q, et al. Anacetrapib and dalcetrapib differentially alters HDL metabolism and macrophage-to-feces reverse cholesterol transport at similar levels of CETP inhibition in hamsters. Eur J Pharmacol. 2014 Oct 5;740:135-43.

  [5] Shinkai H, Maeda K, et al. bis(2-(Acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, and S-(2-(acylamino)phenyl) alkanethioates as novel inhibitors of cholesteryl ester transfer protein. J Med Chem. 2000 Sep 21;43(19):3566-72.

  [6] Kuhlmann O, Heinig K, et al. Dalcetrapib pharmacokinetics and metabolism in the cynomolgus monkey. Xenobiotica. 2011 May;41(5):430-6.

  [7] Kosmas CE, DeJesus E, Rosario D, Vittorio TJ. CETP Inhibition: Past Failures and Future Hopes. Clin Med Insights Cardiol. 2016 Mar 13;10:37-42. doi: 10.4137/CMC.S32667. PMID: 26997876; PMCID: PMC4790583.

  [8] Niesor EJ, Magg C, Ogawa N, Okamoto H, von der Mark E, Matile H, Schmid G, Clerc RG, Chaput E, Blum-Kaelin D, Huber W, Thoma R, Pflieger P, Kakutani M, Takahashi D, Dernick G, Maugeais C. Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport. J Lipid Res. 2010 Dec;51(12):3443-54. doi: 10.1194/jlr.M008706. Epub 2010 Sep 22. PMID: 20861162; PMCID: PMC2975716.

  [9] Shinkai H, Maeda K, Yamasaki T, Okamoto H, Uchida I. bis(2-(Acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, and S-(2-(acylamino)phenyl) alkanethioates as novel inhibitors of cholesteryl ester transfer protein. J Med Chem. 2000 Sep 21;43(19):3566-72. doi: 10.1021/jm000224s. PMID: 11000011.

  [10] Huang Z, Inazu A, Kawashiri MA, Nohara A, Higashikata T, Mabuchi H. Dual effects on HDL metabolism by cholesteryl ester transfer protein inhibition in HepG2 cells. Am J Physiol Endocrinol Metab. 2003 Jun;284(6):E1210-9. doi: 10.1152/ajpendo.00453.2002. Epub 2003 Feb 25. PMID: 12604506.

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