Torcetrapib

• CAT Number: I002898
• CAS Number: 262352-17-0
• Molecular Formula: C₂₆H₂₅F₉N₂O₄
• Molecular Weight: 600.47
• Purity: ≥95%
• Synonyms: ethyl (2R,4S)-4-[[3,5-bis(trifluoromethyl)phenyl]methyl-methoxycarbonylamino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate
• Target: CETP
• Solubility: 10 mM in DMSO
• Storage: 3 years -20C powder
• IC50: 37 nM [1]
• InChI: InChI=1S/C26H25F9N2O4/c1-4-18-12-21(19-11-15(24(27,28)29)6-7-20(19)37(18)23(39)41-5-2)36(22(38)40-3)13-14-8-16(25(30,31)32)10-17(9-14)26(33,34)35/h6-11,18,21H,4-5,12-13H2,1-3H3/t18-,21+/m1/s1
• InChIKey: CMSGWTNRGKRWGS-NQIIRXRSSA-N
• SMILES: CCC1CC(C2=C(N1C(=O)OCC)C=CC(=C2)C(F)(F)F)N(CC3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C(=O)OC

Torcetrapib(CP-529414) is a CETP inhibitor with IC50 of 37 nM, elevates HDL-C and reduces nonHDL-C in plasma.IC50 value: 37 nM [1]Target: CETP inhibitorin vitro: Torcetrapib dose-dependently increases aldosterone release from H295R cells after either 24 or 48 h of treatment with an EC50 of approximately 80 nM, this effect is mediated by calcium channel as calcium channel blockers completely blocks torcetrapib-induced corticoid release and calcium increase. Torcetrapib (1 μM) significantly increases the expression of steroidogenic gene, CYP11B2 and CYP11B1, in H295R cell lines [2].in vivo: Torcetrapib (< 100 mg, daily) changes the plasma distribution of CETP, as the apparent molecular weight of the CETP has shifted to a larger form, by 2 hours after the dose in healthy young subjects. Torcetrapib treatment with 10 mg, 30 mg, 60 mg, and 120 mg daily and 120 mg twice daily results in 16%, 28%, 62%, 73%, and 91% increases in plasma HDL-C, respectively, with no significant changes in TPC in healthy young subjects. [1] Torcetrapib results in an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone, in patients at high cardiovascular risk after 12 months/’ treatment [3]. Torcetrapib (90 mg/kg/day) results in a 70% inhibition of CE transfer in rabbits fed an atherogenic diet. Torcetrapib (90 mg/kg/day) increases mean HDL-C levels by above 3-fold and apoA-I levels by 2.5-fold in plasma in rabbits fed an atherogenic diet. Torcetrapib-treated animal has a multiple-fold increase in HDL-C AUC and a corresponding reduction in aortic lesion area with 60% reduction of aortic free cholesterol (FC) and cholesteryl ester (EC) in rabbits fed an atherogenic diet. Torcetrapib-treated rabbits stimulate free cholesterol efflux to a significantly greater extent than does sera from control rabbits [4].

Reference

1:Effects of Torcetrapib and Statin Treatment on ApoC-III and Apoprotein-Defined Lipoprotein Subclasses (from the ILLUMINATE Trial). Bagdade J, Barter P, Quiroga C, Alaupovic P.Am J Cardiol. 2017 Jun 1;119(11):1753-1756. doi: 10.1016/j.amjcard.2017.02.049. Epub 2017 Mar 18. PMID: 28431663 2:Modulating Drug Release and Enhancing the Oral Bioavailability of Torcetrapib with Solid Lipid Dispersion Formulations. Liu Y, Salituro GM, Lee KJ, Bak A, Leung DH.AAPS PharmSciTech. 2015 Oct;16(5):1091-100. doi: 10.1208/s12249-015-0299-8. Epub 2015 Feb 18. PMID: 25690735 Free PMC Article3:In vitro-in vivo evaluation of lipid based formulations of the CETP inhibitors CP-529,414 (torcetrapib) and CP-532,623. McEvoy CL, Trevaskis NL, Edwards GA, Perlman ME, Ambler CM, Mack MC, Brockhurst B, Porter CJ.Eur J Pharm Biopharm. 2014 Nov;88(3):973-85. doi: 10.1016/j.ejpb.2014.08.006. Epub 2014 Aug 23. PMID: 25152213 4:Raising HDL with CETP inhibitor torcetrapib improves glucose homeostasis in dyslipidemic and insulin resistant hamsters. Briand F, Prunet-Marcassus B, Thieblemont Q, Costard C, Muzotte E, Sordello S, Sulpice T.Atherosclerosis. 2014 Apr;233(2):359-62. doi: 10.1016/j.atherosclerosis.2014.01.028. Epub 2014 Jan 23. PMID: 24530763 5:Identification of a novel, non-tetrahydroquinoline variant of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib, with improved aqueous solubility. Kalgutkar AS, Frederick KS, Hatch HL, Ambler CM, Perry DA, Garigipati RS, Chang GC, Lefker BA, Clark RW, Morehouse LA, Francone O, Hu X.Xenobiotica. 2014 Jul;44(7):591-605. doi: 10.3109/00498254.2013.874611. Epub 2013 Dec 31. PMID: 24380613 6:Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. Fan S, Geng Q, Pan Z, Li X, Tie L, Pan Y, Li X.BMC Syst Biol. 2012 Dec 10;6:152. doi: 10.1186/1752-0509-6-152. PMID: 23228038 Free PMC Article7:HDL cholesterol: all hope is not lost after the torcetrapib setback–emerging therapeutic strategies on the horizon. Verma N, Figueredo VM.Am J Ther. 2014 May-Jun;21(3):222-32. doi: 10.1097/MJT.0b013e318249a1b5. Review. PMID: 22967983 8:Relationship between atorvastatin dose and the harm caused by torcetrapib. Barter PJ, Rye KA, Beltangady MS, Ports WC, Duggan WT, Boekholdt SM, DeMicco DA, Kastelein JJ, Shear CL.J Lipid Res. 2012 Nov;53(11):2436-42. doi: 10.1194/jlr.P026328. Epub 2012 Sep 2. PMID: 22941786 Free PMC Article9:Letter by Knop regarding article, /Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial/. Knop FK.Circulation. 2012 Mar 6;125(9):e428. doi: 10.1161/CIRCULATIONAHA.111.060152. No abstract available. PMID: 22392871 Free Article10:Letter by McGuire and Aguilar regarding article, /Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial/. McGuire DK, Aguilar D.Circulation. 2012 Mar 6;125(9):e427. doi: 10.1161/CIRCULATIONAHA.111.057844. No abstract available. PMID: 22392870 Free Article