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Revision as of 14:38, 18 November 2011 editThe chemistds (talk | contribs)Extended confirmed users5,761 edits added CSID, (Std)InChI & (Std)InChIKey← Previous edit Latest revision as of 13:26, 11 July 2024 edit undoMarbletan (talk | contribs)Extended confirmed users5,418 editsm →ACCELERATE 
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{{Chembox {{Chembox
| Verifiedfields = changed
| verifiedrevid = 461280529
| ImageFile=Evacetrapib.svg | ImageFile=Evacetrapib.svg
| ImageSize=150px | ImageSize=150px
| IUPACName=Trans-4-({(5''S'')-5-methyl}(2-methyl-2''H''-tetrazol-5- yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1''H''-benzazepin-1-yl}methyl) cyclohexanecarboxylic acid | IUPACName=Trans-4-({(5''S'')-5-methyl}(2-methyl-2''H''-tetrazol-5- yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1''H''-benzazepin-1-yl}methyl) cyclohexanecarboxylic acid
| OtherNames = LY2484595 | OtherNames = LY2484595
| Section1 = {{Chembox Identifiers |Section1={{Chembox Identifiers
| CASNo=1186486-62-3 | CASNo=1186486-62-3
| CASNo_Ref = {{cascite|correct|}} | CASNo_Ref = {{cascite|correct|??}}
| PubChem = | PubChem = 49836058
| KEGG = D10121
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 2017179
| UNII = 51XWV9K850
| UNII_Ref = {{fdacite|correct|FDA}}
| KEGG_Ref = {{keggcite|correct|kegg}}
| SMILES = O=C(1CC(CN2CCC(N(CC3=CC(C(F)(F)F)=CC(C(F)(F)F)=C3)C4=NN(C)N=N4)C5=CC(C)=CC(C)=C52)CC1)O | SMILES = O=C(1CC(CN2CCC(N(CC3=CC(C(F)(F)F)=CC(C(F)(F)F)=C3)C4=NN(C)N=N4)C5=CC(C)=CC(C)=C52)CC1)O
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 26286916 | ChemSpiderID = 26286916
| InChI = 1/C31H36F6N6O2/c1-18-11-19(2)27-25(12-18)26(5-4-10-42(27)16-20-6-8-22(9-7-20)28(44)45)43(29-38-40-41(3)39-29)17-21-13-23(30(32,33)34)15-24(14-21)31(35,36)37/h11-15,20,22,26H,4-10,16-17H2,1-3H3,(H,44,45)/t20-,22-,26-/m0/s1 | InChI = 1/C31H36F6N6O2/c1-18-11-19(2)27-25(12-18)26(5-4-10-42(27)16-20-6-8-22(9-7-20)28(44)45)43(29-38-40-41(3)39-29)17-21-13-23(30(32,33)34)15-24(14-21)31(35,36)37/h11-15,20,22,26H,4-10,16-17H2,1-3H3,(H,44,45)/t20-,22-,26-/m0/s1
| InChIKey = IHIUGIVXARLYHP-YBXDKENTBY | InChIKey = IHIUGIVXARLYHP-YBXDKENTBY
⚫ | StdInChI = 1S/C31H36F6N6O2/c1-18-11-19(2)27-25(12-18)26(5-4-10-42(27)16-20-6-8-22(9-7-20)28(44)45)43(29-38-40-41(3)39-29)17-21-13-23(30(32,33)34)15-24(14-21)31(35,36)37/h11-15,20,22,26H,4-10,16-17H2,1-3H3,(H,44,45)/t20-,22-,26-/m0/s1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
⚫ | StdInChIKey = IHIUGIVXARLYHP-YBXDKENTSA-N
⚫ | StdInChI = 1S/C31H36F6N6O2/c1-18-11-19(2)27-25(12-18)26(5-4-10-42(27)16-20-6-8-22(9-7-20)28(44)45)43(29-38-40-41(3)39-29)17-21-13-23(30(32,33)34)15-24(14-21)31(35,36)37/h11-15,20,22,26H,4-10,16-17H2,1-3H3,(H,44,45)/t20-,22-,26-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
⚫ | StdInChIKey = IHIUGIVXARLYHP-YBXDKENTSA-N
}} }}
| Section2 = {{Chembox Properties |Section2={{Chembox Properties
| C=31 | H=36 | F=6 | N=6 | O=2 | C=31 | H=36 | F=6 | N=6 | O=2
| Appearance = | Appearance =
| Density = | Density =
| MeltingPt = | MeltingPt =
| BoilingPt = | BoilingPt =
| Solubility = }} | Solubility = }}
| Section3 = {{Chembox Hazards |Section3={{Chembox Hazards
| MainHazards = | MainHazards =
| FlashPt = | FlashPt =
| Autoignition = }} | AutoignitionPt = }}
}} }}


'''Evacetrapib''' is a ] under development by ] (investigational name '''LY2484595''') that inhibits ], which transfers and thereby increases ] and lowers ]. It is thought that modifying lipoprotein levels modifies the risk of ].<ref name="pmid21957197"/> The first CEPT inhibitor, ], was unsuccesful because it increased levels of the hormone ] and increased ],<ref name="pmid19522058"/> which led to excess cardiac events when it was studied.<ref name="pmid19522058"/> Evacetrapib does not have the same effect.<ref name="pmid21957197">{{cite journal |author=Cao G, Beyer TP, Zhang Y, ''et al.'' |title=Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure |journal=J. Lipid Res. |volume=52 |issue=12 |pages=2169–76 |year=2011 |month=December |pmid=21957197 |doi=10.1194/jlr.M018069 |url=}}</ref> When studied in a small ] in people with elevated LDL and low HDL, significant improvements were noted in their lipid profile.<ref name=Nicholls>{{cite journal | author=Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, Hu B, McErlean E, Nissen SE | title=Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol | journal=JAMA | year=2011 | volume=306 | issue=19 | pages=2099–109 | doi=10.1001/jama.2011.1649}}</ref> '''Evacetrapib''' was a ] under development by ] (investigational name '''LY2484595''') that inhibits ] (]). CETP collects ]s from ]s (VLDL) or ]s (LDL) and exchanges them for ]s from ]s (HDL), and vice versa, but primarily increasing high-density lipoprotein and lowering low-density lipoprotein. It is thought that modifying lipoprotein levels modifies the risk of ].<ref name="pmid21957197"/> The first CETP inhibitor, ], was unsuccessful because it increased levels of the hormone ] and increased ],<ref name="pmid19522058"/> which led to excess cardiac events when it was studied.<ref name="pmid19522058"/> Evacetrapib does not have the same effect.<ref name="pmid21957197">{{cite journal |vauthors=Cao G, Beyer TP, Zhang Y |title=Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure |journal=J. Lipid Res. |volume=52 |issue=12 |pages=2169–76 |date=December 2011 |pmid=21957197 |doi=10.1194/jlr.M018069 |doi-access=free |pmc=3220285|display-authors=etal}}</ref> When studied in a small ] in people with elevated LDL and low HDL, significant improvements were noted in their lipid profile.<ref name=Nicholls>{{cite journal |vauthors=Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, Hu B, McErlean E, Nissen SE | title=Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol | journal=JAMA | year=2011 | volume=306 | issue=19 | pages=2099–109 | doi=10.1001/jama.2011.1649| pmid=22089718 | doi-access= }}</ref>


Together with ] and ], evacetrapib is the third CETP inhibitor currently being investigated.<ref name="pmid21957197"/> Despite the problems with torcetrapib, it is thought that CETP inhibitors are still likely to be useful in the treatment of dyslipidemia and the prevention of cardiovascular disease.<ref name="pmid19522058">{{cite journal |author=Joy T, Hegele RA |title=The end of the road for CETP inhibitors after torcetrapib? |journal=Curr. Opin. Cardiol. |volume=24 |issue=4 |pages=364–71 |year=2009 |month=July |pmid=19522058 |doi=10.1097/HCO.0b013e32832ac166}}</ref> Evacetrapib evaluation for treatment of high-risk vascular disease was discontinued due to lack of efficacy, as had already happened in the past with two other CETP inhibitors (] and ]<ref name="pmid23126252">{{cite journal |author=Schwartz GG |title=Effects of dalcetrapib in patients with a recent acute coronary syndrome. |journal=N Engl J Med |volume=367 |issue=22 |pages=2089–99 |date=Nov 2015 |pmid=23126252|display-authors=etal |doi=10.1056/NEJMoa1206797|url=http://www.zora.uzh.ch/75761/1/NEJMoa1206797.pdf }}</ref>) due to increased deaths and little identifiable cardiovascular benefit (despite substantial increases in HDL). Some hypothesize that CETP inhibitors may still be useful in the treatment of dyslipidemia, though significant caution is warranted.<ref name="pmid19522058">{{cite journal |vauthors=Joy T, Hegele RA |title=The end of the road for CETP inhibitors after torcetrapib? |journal=Curr. Opin. Cardiol. |volume=24 |issue=4 |pages=364–71 |date=July 2009 |pmid=19522058 |doi=10.1097/HCO.0b013e32832ac166|s2cid=6965741 }}</ref> ] is the fourth CETP inhibitor being tried for cardiovascular benefit <ref name="pmid21957197"/>

== Trials ==

===ACCELERATE===
In a 2014 study in 165 Japanese patients evacetrapib decreased CETP activity alone or in combination with ].<ref>{{Cite journal|title = Efficacy, safety, tolerability, and pharmacokinetic profile of evacetrapib administered as monotherapy or in combination with atorvastatin in Japanese patients with dyslipidemia|date = Jun 15, 2014|journal = Am J Cardiol|doi = 10.1016/j.amjcard.2014.03.045|pmid = 24786356 |volume=113 |issue = 12|pages=2021–9|last1 = Teramoto|first1 = Tamio|last2 = Takeuchi|first2 = Masakazu|last3 = Morisaki|first3 = Yoji|last4 = Ruotolo|first4 = Giacomo|last5 = Krueger|first5 = Kathryn A.|doi-access = free}}</ref>

Phase III trial was terminated due to futility.<ref>{{Cite web|url = https://www.acc.org/latest-in-cardiology/clinical-trials/2016/03/29/22/34/accelerate|title = Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes - ACCELERATE
}}</ref><ref>{{Cite web|url = http://www.clinicaltrials.gov/show/NCT01687998|title = A Study of Evacetrapib in High-Risk Vascular Disease (ACCELERATE)}}</ref> ACCELERATE studied evacetrapib in participants with high-risk vascular disease (previous myocardial infarction, stroke or peripheral vascular disease, or several cardiovascular risk factors). An interim analysis performed in October 7 led the Data Monitoring Committee to support a recommendation to stop the study as the totality of evidence suggested that evacetrapib was unlikely to be superior to placebo.<ref>{{Cite web|url = https://investor.lilly.com/releasedetail.cfm?releaseid=936130|title = Lilly to Discontinue Development of Evacetrapib for High-Risk Atherosclerotic Cardiovascular Disease|archive-url = https://web.archive.org/web/20151103172729/https://investor.lilly.com/releasedetail.cfm?ReleaseID=936130|archive-date = 2015-11-03|url-status = dead}}</ref> ACCENTUATE is studying patients with hyperlipidemia or diabetes.<ref>{{Cite web|url = http://www.clinicaltrials.gov/ct2/show/NCT02227784|title = Study of Evacetrapib (LY2484595) in Participants With High Cholesterol (ACCENTUATE)| date=25 September 2019 }}</ref>

On April 3, 2016 at the ] cardiologists first saw the data for Eli Lilly's ACCELERATE trial of evacetrapib involving 12,000 patients.<ref name="nytimes_2016">{{cite web | url=https://www.nytimes.com/2016/04/04/health/dashing-hopes-study-shows-cholesterol-drug-has-no-benefits.html?mabReward=CTM&moduleDetail=recommendations-1&action=click&contentCollection=Opinion&region=Footer&module=WhatsNext&version=WhatsNext&contentID=WhatsNext&src=recg&pgtype=article | title=Dashing Hopes, Study Shows a Cholesterol Drug Had No Effect on Heart Health | work=New York Times | date=3 April 2016 | access-date=4 April 2016 | author=Kolata, Gina}}</ref> They were "stunned" by the result which showed there was no benefit from taking evacetrapib—434 participants who took evacetrapib died from "cardiovascular disease, such as a heart attack or a stroke" and 444 participants who took a placebo died.<ref name="nytimes_2016" /> The ACCELERATE trial led by Stephen J. Nicholls who observed,<ref name="nytimes_2016" />

{{blockquote|"“It’s the most mind-boggling question. How can a drug that lowers something that is associated with benefit not show any benefit?"|Stephen J. Nicholls 2016}}


==References== ==References==
{{reflist}} {{reflist}}


] {{Lipid modifying agents}}

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