Dalcetrapib

Dalcetrapib
Names
IUPAC name
S-[2-({[1-(2-ethylbutyl)cyclohexyl]carbonyl}amino)phenyl] 2-methylpropanethioate
Identifiers
211513-37-0
3D model (Jmol) Interactive image
Interactive image
ChEMBL ChEMBL313006
ChemSpider 5293737
PubChem 6918540
UNII 3D050LIQ3H YesY
Properties
C23H35NO2S
Molar mass 389.5945
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Dalcetrapib or JTT-705 is a CETP inhibitor which was being developed by Hoffmann–La Roche until May 2012.[1][2] The drug was aimed at raising the blood levels of "good cholesterol" (cholesterol carried in HDL particles, aka HDL-C).[3] 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.[4]

A 24-week clinical trial showed that dalcetrapib did increase HDL-C levels, supporting the agent's desired effect.[5] Further, the dal-PLAQUE phase IIb trial found evidence of plaque reduction.[6] Plaque reduction is an anticipated observation following an increase in HDL.

As of 2010 five phase II trials had started and there was no evidence of the raised blood pressure seen with torcetrapib.[5]

dal-VESSEL phase IIb trial found no evidence of flow-mediated dilatation improvement. A 17% increase of Lp-PLA2 mass level was noted.[7] Lp-PLA2 is associated with coronary heart disease and stroke.

dal-OUTCOMES phase III trial passed its first interim review in July, 2011,[8] however, development was halted on May 7, 2012 “due to a lack of clinically meaningful efficacy.”.[2]

The results of dal-OUTCOMES III were published in November, 2012.[9]

A pharmacogenomic GWAS study reported that patients from the dal-OUTCOMES study bearing a protective allele at SNP rs1967309 in the ADCY9 gene may have benefited from dalcetrapib therapy.[10] Changes in inflammation and cholesterol efflux capacity may in part explain the benefits associated with the protective genotype. [11] The Dal-GenE trial is currently validating these observations. This clinical trial is a randomized placebo-controlled study to evaluate the effects of dalcetrapib on cardiovascular risk in patients with recent acute coronary syndrome bearing the protective genotype.[12]

See also

References

  1. ↑ Huang Z; Inazu A; Nohara A; Higashikata T; Mabuchi H (December 2002). "Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia". Clin. Sci. 103 (6): 587–594. PMID 12444911.
  2. 1 2 Simeon Bennett & Naomi Kresge. "Roche Drops After Halting Cholesterol Drug Development". Bloomberg.
  3. ↑ Michelle Fay Cortez (November 5, 2012), "Roche's Good Cholesterol Drug Shows Negative Side Effects", Bloomberg Businessweek, retrieved November 6, 2012
  4. ↑ "NIH stops clinical trial on combination cholesterol treatment". National Institute of Health. NHLBI. Retrieved June 2, 2011.
  5. 1 2 Stein; et al. (2010). "Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial". Eur. Heart J. 31 (4): 480–4888. doi:10.1093/eurheartj/ehp601. PMC 2821630Freely accessible. PMID 20097702.
  6. ↑ Zahi A Fayad; et al. (2011). "Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial". The Lancet. 378 (9802): 1547–1559. doi:10.1016/S0140-6736(11)61383-4.
  7. ↑ Thomas F. Lüscher; et al. (2012). "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. 33: 857–865. doi:10.1093/eurheartj/ehs019.
  8. ↑ Gail Parziale. "Dalcetrapib and Anacetrapib: a Tale of Two CETPs".
  9. ↑ Schwartz, G. G.; Olsson, A. G.; Abt, M.; Ballantyne, C. M.; Barter, P. J.; Brumm, J.; Chaitman, B. R.; Holme, I. M.; Kallend, D.; Leiter, L. A.; Leitersdorf, E.; McMurray, J. J. V.; Mundl, H.; Nicholls, S. J.; Shah, P. K.; Tardif, J. C.; Wright, R. S.; Dal-Outcomes, I. (2012). "Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome". New England Journal of Medicine. 367 (22): 2089–2099. doi:10.1056/NEJMoa1206797. PMID 23126252.
  10. ↑ Tardif, Jean-Claude; Rhéaume, Eric; Lemieux Perreault, Louis-Philippe; Grégoire, Jean C.; Feroz Zada, Yassamin; Asselin, Géraldine; Provost, Sylvie; Barhdadi, Amina; Rhainds, David (2015-04-01). "Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib". Circulation. Cardiovascular Genetics. 8 (2): 372–382. doi:10.1161/CIRCGENETICS.114.000663. ISSN 1942-3268. PMID 25583994.
  11. ↑ Tardif, Jean-Claude; Rhainds, David; Brodeur, Mathieu; Feroz Zada, Yassamin; Fouodjio, René; Provost, Sylvie; Boulé, Marie; Alem, Sonia; Grégoire, Jean C. (2016-08-01). "Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation: Concordance With Clinical Outcomes". Circulation. Cardiovascular Genetics. 9 (4): 340–348. doi:10.1161/CIRCGENETICS.116.001405. ISSN 1942-3268. PMC 4982759Freely accessible. PMID 27418594.
  12. ↑ "Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-12-02.
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