Anacetrapib
| Anacetrapib | |
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(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl}methyl)-4-methyl-1,3-oxazolidin-2-one |
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| Identifiers | |
| CAS number | 875446-37-0  |
| PubChem | 11556427 |
| ChemSpider | 9731205 |
| KEGG | D08855 |
| Jmol-3D images | Image 1 |
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| Properties | |
| Molecular formula | C30H25F10NO3 |
| Molar mass | 637.51 g·mol−1 |
 (verify) (what is:  / ?)Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| Infobox references | |
Anacetrapib (USAN,[1] pINN; codenamed MK-0859, Merck) is a CETP inhibitor being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease.
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[edit] Clinical trials
At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New York, Oct 4-7, 2007), Merck reported on a Phase IIb study. The eight week study reported dosage correlated reduction in LDL-C and increases in HDL-C levels with no corresponding increases in blood pressure in any cohort. The increase in HDL was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133 percent at doses of 10 mg, 40 mg, 150 mg and 300 mg.
Merck performed a dose-ranging study of anacetrapib, with the results presented in 2009[2]
[edit] Phase III trial (DEFINE)
Merck started a Phase III trial to assess the drug's effects on LDL, HDL, clinically measurable cardiovascular events, and safety;[3] It was code-named DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib), and was described as a medium sized safety and efficacy trial.[4]
Early results from the DEFINE trial were presented on November 17 at AHA2010, a meeting of the American Heart Association. At 100 mg dosage, LDL decreased by 36%, lipoprotein(a) decreased by 36.4%, while HDL increased by 138%. Systolic blood pressure showed no increase, and there was no association with increased CVD death or events. [5]
Cardiologist Steve Nissen described DEFINE as a medium-sized safety trial intended to find out "whether anacetrapib would show the same increase in adverse cardiovascular events that was seen with torcetrapib." Fortunately, anacetrapib did not. In his opinion the DEFINE study was too small to show a clear benefit, but the trends in the major adverse cardiovascular events were going in the right direction.[6]
Two year follow up due to complete by December 2012.
[edit] Phase III trial (REVEAL)
The REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification) will assess whether there is clinical benefit associated with anacetrapib. REVEAL is currently recruiting 30,000 participants for a randomized, double-blinded, placebo- controlled trial.
The study will compare patients with a history of vascular disease (such as heart disease, cerebrovascular disease, and peripheral vascular disease) on 100 mg of anacetrapib daily to those on placebo, to determine if the addition of anacetrapib reduces the risk of major coronary events (such as heart attack, death from heart disease, or requiring a coronary revascularization.) Data will be collected through 2017. [7]
[edit] See also
- Torcetrapib, another CETP inhibitor, which was developed by Pfizer but caused unacceptable increases in blood pressure and had net cardiovascular detriment.
[edit] References
- ^ "Statement on a nonproprietary name adopted by the USAN Council: Anacetrapib". American Medical Association. 2007. http://www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf. Retrieved 2008-01-19.
- ^ Bloomfield D, Carlson GL, Sapre A et al. (October 2009). "Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and co-administered with atorvastatin in dyslipidemic patients". Am. Heart J. 157 (2): 352–360. doi:10.1016/j.ahj.2008.09.022. PMID 19185645. http://www.ahjonline.com/article/PIIS0002870308008284/fulltext.
- ^ "Phase III Study to Assess the Tolerability and Efficacy of Anacetrapib in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease (DEFINE)". ClinicalTrials.gov. U.S. NIH. http://clinicaltrials.gov/ct2/show/NCT00685776.
- ^ Cannon CP, Dansky HM, Davidson M, et al. (October 2009). "Design of the DEFINE trial: determining the Efficacy and tolerability of CETP Inhibition with AnacEtrapib". Am. Heart J. 158 (4): 513–519.e3. doi:10.1016/j.ahj.2009.07.028. PMID 19781408. http://www.ncbi.nlm.nih.gov/pubmed/19781408.
- ^ Cannon, Christopher, S. Shah et al (November 17, 2010). "Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease". New England Journal of Medicine (published online) 363 (25): 2406. doi:10.1056/NEJMoa1009744. http://www.nejm.org/doi/full/10.1056/NEJMoa1009744.
- ^ O'Riordan, Michael (November 17, 2010). "DEFINE: Large effects on LDL and HDL cholesterol with CETP inhibitor anacetrapib". theheart.org. http://www.theheart.org/article/1151979.do.
- ^ National Institute of Health (January 30, 2012). "REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification". clinicaltrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT01252953?term=reveal&rank=1.
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PROCESS FOR SYNTHESIZING A CETP INHIBITOR
PROCESS FOR SYNTHESIZING A CETP INHIBITOR Inventor(s): MILLER ROSS A [US]; COTE AARON S [US] + (MILLER, ROSS, A, ; COTE, AARON, S) Applicant(s): MERCK & CO INC [US]; MILLER ROSS A [US]; COTE AARON S [US] + (MERCK & CO., INC, ; MILLER, ROSS, A, ; COTE, AARON, S) Classification: - international: A61K31/421; C07D263/22 - European: C07D263/24
Application number: WO2006US25511 20060629 Priority number(s): US20050696233P 20050701 Also published as: US2010041724 (A1) US7863307 (B2) JP2009500341 (A) EP1901741 (A1) EP1901741 (A4) more
Abstract of WO2007005572 (A1) An efficient process is disclosed for producing a compound that is an inhibitor of CETP. The last step of the process is the coupling of an oxazolidinone derivative with a biphenyl moiety to provide a compound of formula (I). In a specific embodiment of this synthesis, a crystalline product is produced which is characterized as a non-solvated crystalline polymorph.
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