Dalcetrapib
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MedKoo CAT#: 319508

CAS#: 211513-37-0

Description: Dalcetrapib, aslo known as JTT-705, is a CETP inhibitor. The drug was aimed at raising the blood levels of "good cholesterol" (cholesterol carried in HDL particles, aka HDL-C). Prevailing observations indicate that high HDL levels correlate with better overall cardiovascular health, though it remains unclear whether raising HDL levels consequently leads to an increase in cardiovascular health. Development of this drug was halted on May 7, 2012 “due to a lack of clinically meaningful efficacy.


Chemical Structure

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Dalcetrapib
CAS# 211513-37-0

Theoretical Analysis

MedKoo Cat#: 319508
Name: Dalcetrapib
CAS#: 211513-37-0
Chemical Formula: C23H35NO2S
Exact Mass: 389.24
Molecular Weight: 389.598
Elemental Analysis: C, 70.91; H, 9.06; N, 3.60; O, 8.21; S, 8.23

Price and Availability

Size Price Availability Quantity
10mg USD 350 2 weeks
25mg USD 700 2 weeks
50mg USD 1150 2 Weeks
Bulk inquiry

Synonym: JTT-705; JTT705; JTT 705; RO-4607381; RO4607381; RO 4607381; Dalcetrapib.

IUPAC/Chemical Name: S-[2-[[1-(2-ethylbutyl)cyclohexanecarbonyl]amino]phenyl] 2-methylpropanethioate

InChi Key: YZQLWPMZQVHJED-UHFFFAOYSA-N

InChi Code: InChI=1S/C23H35NO2S/c1-5-18(6-2)16-23(14-10-7-11-15-23)22(26)24-19-12-8-9-13-20(19)27-21(25)17(3)4/h8-9,12-13,17-18H,5-7,10-11,14-16H2,1-4H3,(H,24,26)

SMILES Code: CC(C)C(SC1=CC=CC=C1NC(C2(CC(CC)CC)CCCCC2)=O)=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Product Data:
Biological target: Dalcetrapib (JTT-705; RO-4607381) is a rhCETP inhibitor with IC50 of 0.2 μM that increases the plasma HDL cholesterol.
In vitro activity: Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication was investigated. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of -8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC50 values of 14.4 ± 3.3 μM and an EC50 of 17.5 ± 3.5 μM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal dalcetrapib-thiol concentration of approximately 100 times below the IC50 of 14.4 μM, suggesting stable protease-drug interaction. The inhibitory effect of dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19. Reference: ACS Omega. 2021 Jun 17;6(25):16584-16591. https://pubmed.ncbi.nlm.nih.gov/34235330/
In vivo activity: Animals were fed JTT-705-containing mouse pellets for 6 days, and each animal received an estimated dose of 0.6 mg of compound/day. As shown in Fig. 8, treatment with JTT-705 completely abrogated LPS-dependent TNFα production and resulted in serum levels of TNFα indistinguishable from those measured in the PMB-treated animals. However, reduction of TNFα did not result in protection against the lethal effects of endotoxic shock, since groups treated with JTT-705 displayed a mortality at 72 h postinoculation similar (90%) to that detected in nontreated animals. Overall, oral intake of JTT-705 significantly inhibited endotoxintriggered tumor necrosis factor alpha production in mice. Reference: J Biol Chem. 2009 Jul 17;284(29):19493-500. https://pubmed.ncbi.nlm.nih.gov/19473973/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 49.0 125.77
Ethanol 54.0 138.60

Preparing Stock Solutions

The following data is based on the product molecular weight 389.60 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Niesor EJ, Boivin G, Rhéaume E, Shi R, Lavoie V, Goyette N, Picard ME, Perez A, Laghrissi-Thode F, Tardif JC. Inhibition of the 3CL Protease and SARS-CoV-2 Replication by Dalcetrapib. ACS Omega. 2021 Jun 17;6(25):16584-16591. doi: 10.1021/acsomega.1c01797. PMID: 34235330; PMCID: PMC8230949. 2. Mancek-Keber M, Gradisar H, Iñigo Pestaña M, Martinez de Tejada G, Jerala R. Free thiol group of MD-2 as the target for inhibition of the lipopolysaccharide-induced cell activation. J Biol Chem. 2009 Jul 17;284(29):19493-500. doi: 10.1074/jbc.M109.003756. Epub 2009 May 27. PMID: 19473973; PMCID: PMC2740575.
In vitro protocol: 1. Niesor EJ, Boivin G, Rhéaume E, Shi R, Lavoie V, Goyette N, Picard ME, Perez A, Laghrissi-Thode F, Tardif JC. Inhibition of the 3CL Protease and SARS-CoV-2 Replication by Dalcetrapib. ACS Omega. 2021 Jun 17;6(25):16584-16591. doi: 10.1021/acsomega.1c01797. PMID: 34235330; PMCID: PMC8230949.
In vivo protocol: 1. Mancek-Keber M, Gradisar H, Iñigo Pestaña M, Martinez de Tejada G, Jerala R. Free thiol group of MD-2 as the target for inhibition of the lipopolysaccharide-induced cell activation. J Biol Chem. 2009 Jul 17;284(29):19493-500. doi: 10.1074/jbc.M109.003756. Epub 2009 May 27. PMID: 19473973; PMCID: PMC2740575.

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1: Johns DG, Chen Y, Wang SP, Castro-Perez J, Previs SF, Roddy TP. Inhibition of cholesteryl ester transfer protein increases cholesteryl ester content of large HDL independently of HDL-to-HDL homotypic transfer: in vitro vs in vivo comparison using anacetrapib and dalcetrapib. Eur J Pharmacol. 2015 Sep 5;762:256-62. doi: 10.1016/j.ejphar.2015.05.061. Epub 2015 Jun 3. PubMed PMID: 26049012.

2: Tardif JC, Rhéaume E, Lemieux Perreault LP, Grégoire JC, Feroz Zada Y, Asselin G, Provost S, Barhdadi A, Rhainds D, L'Allier PL, Ibrahim R, Upmanyu R, Niesor EJ, Benghozi R, Suchankova G, Laghrissi-Thode F, Guertin MC, Olsson AG, Mongrain I, Schwartz GG, Dubé MP. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet. 2015 Apr;8(2):372-82. doi: 10.1161/CIRCGENETICS.114.000663. Epub 2015 Jan 11. PubMed PMID: 25583994.

3: Niesor EJ, Kallend D, Bentley D, Kastelein JJ, Kees Hovingh G, Stroes ES. Treatment of low HDL-C subjects with the CETP modulator dalcetrapib increases plasma campesterol only in those without ABCA1 and/or ApoA1 mutations. Lipids. 2014 Dec;49(12):1245-9. doi: 10.1007/s11745-014-3956-x. Epub 2014 Oct 4. PubMed PMID: 25281277.

4: Briand F, Thieblemont Q, Muzotte E, Burr N, Urbain I, Sulpice T, Johns DG. 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. doi: 10.1016/j.ejphar.2014.06.022. Epub 2014 Jul 5. PubMed PMID: 25008069.

5: Takubo H, Ishikawa T, Kuhlmann O, Nemoto H, Noguchi T, Nanayama T, Komura H, Kogayu M. Pharmacokinetics and disposition of dalcetrapib in rats and monkeys. Xenobiotica. 2014 Dec;44(12):1117-26. doi: 10.3109/00498254.2014.932471. Epub 2014 Jun 23. PubMed PMID: 24954481.

6: Tomoda H. Dalcetrapib in patients with an acute coronary syndrome. N Engl J Med. 2013 Feb 28;368(9):869. doi: 10.1056/NEJMc1300057#SA1. PubMed PMID: 23445099.

7: Schwartz GG, Olsson AG, Barter PJ. Dalcetrapib in patients with an acute coronary syndrome. N Engl J Med. 2013 Feb 28;368(9):869-70. doi: 10.1056/NEJMc1300057. PubMed PMID: 23445098.

8: Phelan M, Anzures-Cabrera J, Carlile DJ, Rowell L, Kuhlmann O, Arold G, Robson R, Bentley D. Effect of hepatic and renal impairment on the pharmacokinetics of dalcetrapib: altered distribution of the active thiol? Clin Pharmacokinet. 2013 Apr;52(4):255-65. doi: 10.1007/s40262-013-0035-z. PubMed PMID: 23400900.

9: Aceves Baldó P, Anzures-Cabrera J, Bentley D. In vivo evaluation of drug-drug interactions linked to UGT inhibition: the effect of probenecid on dalcetrapib pharmacokinetics. Int J Clin Pharmacol Ther. 2013 Mar;51(3):215-8. doi: 10.5414/CP201766. PubMed PMID: 23357838.

10: Lim GB. Lipids. Dalcetrapib raises HDL-cholesterol level, but does not reduce cardiac risk. Nat Rev Cardiol. 2013 Jan;10(1):5. doi: 10.1038/nrcardio.2012.171. Epub 2012 Nov 20. PubMed PMID: 23165074.

11: Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012 Nov 29;367(22):2089-99. doi: 10.1056/NEJMoa1206797. Epub 2012 Nov 5. PubMed PMID: 23126252.

12: Goldberg AS, Hegele RA. Cholesteryl ester transfer protein inhibitors for dyslipidemia: focus on dalcetrapib. Drug Des Devel Ther. 2012;6:251-9. doi: 10.2147/DDDT.S34976. Epub 2012 Sep 24. Review. PubMed PMID: 23055695; PubMed Central PMCID: PMC3460676.

13: Gross G, Tardio J, Kuhlmann O. Solubility and stability of dalcetrapib in vehicles and biological media. Int J Pharm. 2012 Nov 1;437(1-2):103-9. doi: 10.1016/j.ijpharm.2012.07.071. Epub 2012 Aug 4. PubMed PMID: 22884829.

14: Rhainds D, Arsenault BJ, Brodeur MR, Tardif JC. An update on the clinical development of dalcetrapib (RO4607381), a cholesteryl ester transfer protein modulator that increases HDL cholesterol levels. Future Cardiol. 2012 Jul;8(4):513-31. doi: 10.2217/fca.12.25. Review. PubMed PMID: 22871191.

15: Hooper AJ, Burnett JR. Dalcetrapib , a cholesteryl ester transfer protein modulator. Expert Opin Investig Drugs. 2012 Sep;21(9):1427-32. doi: 10.1517/13543784.2012.699040. Epub 2012 Jun 24. PubMed PMID: 22725099.

16: Heinig K, Bucheli F, Kuhlmann O, Zell M, Pähler A, Zwanziger E, Gross G, Tardio J, Ishikawa T, Yamashita T. Determination of dalcetrapib by liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal. 2012 Jul;66:314-24. doi: 10.1016/j.jpba.2012.03.056. Epub 2012 Apr 6. PubMed PMID: 22541249.

17: Young A, Anzures-Cabrera J, Derks M. No clinically relevant drug-drug interactions when dalcetrapib is co-administered with a monophasic oral contraceptive (Microgynon® 30). Int J Clin Pharmacol Ther. 2012 Apr;50(4):248-56. PubMed PMID: 22456295.

18: Ballantyne CM, Miller M, Niesor EJ, Burgess T, Kallend D, Stein EA. Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: results of a phase IIb dose-ranging study. Am Heart J. 2012 Mar;163(3):515-21, 521.e1-3. doi: 10.1016/j.ahj.2011.11.017. PubMed PMID: 22424025.

19: Lim GB. Pharmacotherapy. Elevating HDL-cholesterol levels with dalcetrapib is safe. Nat Rev Cardiol. 2012 Mar 6;9(5):257. doi: 10.1038/nrcardio.2012.31. PubMed PMID: 22392063.

20: Lüscher TF, Taddei S, Kaski JC, Jukema JW, Kallend D, Münzel T, Kastelein JJ, Deanfield JE; dal-VESSEL Investigators. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. Eur Heart J. 2012 Apr;33(7):857-65. doi: 10.1093/eurheartj/ehs019. Epub 2012 Feb 16. PubMed PMID: 22345126; PubMed Central PMCID: PMC3345558.