Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C19H29NOS |
| Molecular Weight | 319.505 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CCC(CC)CC1(CCCCC1)C(=O)NC2=C(S)C=CC=C2
InChI
InChIKey=OVRLABAFXJPIMU-UHFFFAOYSA-N
InChI=1S/C19H29NOS/c1-3-15(4-2)14-19(12-8-5-9-13-19)18(21)20-16-10-6-7-11-17(16)22/h6-7,10-11,15,22H,3-5,8-9,12-14H2,1-2H3,(H,20,21)
DescriptionCurator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/20861162
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/20861162
Dalcetrapib (JTT-705) is a modulator than an inhibitor of cholesteryl ester transfer protein (CETP) activity and it may interact with and decrease CETP activity by a unique mechanism without an off-target effect. Dalcetrapib increased high-density lipoprotein (HDL) cholesterol levels but did not reduce the risk of cardiovascular events. It is in phase III of clinical trials for the treatment of acute coronary syndrome.
Originator
Approval Year
Doses
| Dose | Population | Adverse events |
|---|---|---|
600 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: |
unhealthy, ADULT n = 7938 Health Status: unhealthy Condition: acute coronary syndrome Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7938 Sources: |
Disc. AE: Diarrhea... Other AEs: Hypertension... AEs leading to discontinuation/dose reduction: Diarrhea (1.4%) Other AEs:Hypertension (serious, 0.6%) Sources: |
3900 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 3900 mg, 1 times / day Route: oral Route: multiple Dose: 3900 mg, 1 times / day Sources: |
healthy n = 8 Health Status: healthy Sex: M Food Status: UNKNOWN Population Size: 8 Sources: |
Other AEs: Flatulence, upper abdominal pai... Other AEs: Flatulence (25%) Sources: upper abdominal pai (38%) Nausea (13%) diarrhoea (75%) |
4500 mg single, oral (unknown) Highest studied dose |
healthy n = 11 Health Status: healthy Sex: M Food Status: UNKNOWN Population Size: 11 Sources: |
Other AEs: diarrhoea, nausea... |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Diarrhea | 1.4% Disc. AE |
600 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: |
unhealthy, ADULT n = 7938 Health Status: unhealthy Condition: acute coronary syndrome Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7938 Sources: |
| Hypertension | serious, 0.6% | 600 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: |
unhealthy, ADULT n = 7938 Health Status: unhealthy Condition: acute coronary syndrome Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7938 Sources: |
| Nausea | 13% | 3900 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 3900 mg, 1 times / day Route: oral Route: multiple Dose: 3900 mg, 1 times / day Sources: |
healthy n = 8 Health Status: healthy Sex: M Food Status: UNKNOWN Population Size: 8 Sources: |
| Flatulence | 25% | 3900 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 3900 mg, 1 times / day Route: oral Route: multiple Dose: 3900 mg, 1 times / day Sources: |
healthy n = 8 Health Status: healthy Sex: M Food Status: UNKNOWN Population Size: 8 Sources: |
| upper abdominal pai | 38% | 3900 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 3900 mg, 1 times / day Route: oral Route: multiple Dose: 3900 mg, 1 times / day Sources: |
healthy n = 8 Health Status: healthy Sex: M Food Status: UNKNOWN Population Size: 8 Sources: |
| diarrhoea | 75% | 3900 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 3900 mg, 1 times / day Route: oral Route: multiple Dose: 3900 mg, 1 times / day Sources: |
healthy n = 8 Health Status: healthy Sex: M Food Status: UNKNOWN Population Size: 8 Sources: |
| nausea | 18% | 4500 mg single, oral (unknown) Highest studied dose |
healthy n = 11 Health Status: healthy Sex: M Food Status: UNKNOWN Population Size: 11 Sources: |
| diarrhoea | 45% | 4500 mg single, oral (unknown) Highest studied dose |
healthy n = 11 Health Status: healthy Sex: M Food Status: UNKNOWN Population Size: 11 Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| [CETP inhibitor]. | 2001 Mar |
|
| The Yin and Yang of cholesteryl ester transfer protein and atherosclerosis. | 2002 Dec |
|
| Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia. | 2002 Dec |
|
| Effect of HDL, from Japanese white rabbit administered a new cholesteryl ester transfer protein inhibitor JTT-705, on cholesteryl ester accumulation induced by acetylated low density lipoprotein in J774 macrophage. | 2002 May |
|
| Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. | 2002 May 7 |
|
| Effect of JTT-705 on cholesteryl ester transfer protein and plasma lipid levels in normolipidemic animals. | 2003 Apr 11 |
|
| Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. | 2003 Feb 1 |
|
| Dual effects on HDL metabolism by cholesteryl ester transfer protein inhibition in HepG2 cells. | 2003 Jun |
|
| Role of CETP inhibitors in the treatment of dyslipidemia. | 2004 Dec |
|
| Inhibition of cholesteryl ester transfer protein increases serum apolipoprotein (apo) A-I levels by increasing the synthesis of apo A-I in rabbits. | 2004 Feb |
|
| JTT-705. Japan Tobacco. | 2004 Mar |
|
| S-(2-(acylamino)phenyl) 2,2-dimethylpropanethioates as CETP inhibitors. | 2004 May 17 |
|
| Consequences of cholesteryl ester transfer protein inhibition in patients with familial hypoalphalipoproteinemia. | 2005 Sep |
|
| Are human CETP mutations and CETP-inhibiting drugs a good or a bad deal? | 2006 Aug |
|
| Cholesteryl ester transfer protein inhibition, high-density lipoprotein metabolism and heart disease risk reduction. | 2006 Aug |
|
| Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease. | 2006 Sep |
|
| The role of CETP inhibition in dyslipidemia. | 2007 Aug |
|
| Inhibition of CETP as a novel therapeutic strategy for reducing the risk of atherosclerotic disease. | 2007 Jan |
|
| Cholesteryl ester transfer protein promotes the formation of cholesterol-rich remnant like lipoprotein particles in human plasma. | 2007 Jan |
|
| Cholesteryl ester transfer protein inhibition and HDL increase: has the dream ended? | 2008 Apr |
|
| Is raising HDL a futile strategy for atheroprotection? | 2008 Feb |
|
| Gateways to clinical trials. July-August 2008. | 2008 Jul-Aug |
|
| Gateways to clinical trials. | 2008 May |
|
| HDL metabolism and CETP inhibition. | 2008 May-Jun |
|
| JTT-705: is there still future for a CETP inhibitor after torcetrapib? | 2008 Oct |
|
| Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia. | 2009 |
|
| Free thiol group of MD-2 as the target for inhibition of the lipopolysaccharide-induced cell activation. | 2009 Jul 17 |
|
| The pharmacology and off-target effects of some cholesterol ester transfer protein inhibitors. | 2009 Nov 16 |
|
| Gateways to clinical trials. | 2009 Sep |
|
| MARCO, a macrophage scavenger receptor highly expressed in rodents, mediates dalcetrapib-induced uptake of lipids by rat and mouse macrophages. | 2010 Apr |
|
| Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. | 2010 Aug |
|
| Lack of clinically relevant drug-drug interactions when dalcetrapib is co-administered with ezetimibe. | 2010 Dec |
|
| Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport. | 2010 Dec |
|
| Mulling over the odds of CETP inhibition. | 2010 Feb |
|
| Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. | 2010 Feb |
|
| Functional assessment of HDL: Moving beyond static measures for risk assessment. | 2010 Feb |
|
| [HDL and CETP in atherogenesis]. | 2010 Feb |
|
| Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. | 2010 Jan |
|
| High density lipoproteins-based therapies for cardiovascular disease. | 2010 Jul |
|
| High-density lipoprotein-mediated anti-atherosclerotic and endothelial-protective effects: a potential novel therapeutic target in cardiovascular disease. | 2010 May |
|
| Good news for 'good' cholesterol. | 2010 Nov 18 |
|
| No clinically relevant drug-drug interactions when dalcetrapib is co-administered with atorvastatin. | 2010 Oct |
|
| Low high-density lipoprotein cholesterol: current status and future strategies for management. | 2010 Oct 29 |
|
| Update on CETP inhibition. | 2010 Sep-Oct |
|
| Insights from recent meta-analysis: role of high-density lipoprotein cholesterol in reducing cardiovascular events and rates of atherosclerotic disease progression. | 2010 Sep-Oct |
|
| Monitoring Cyp2b10 mRNA expression at cessation of 2-year carcinogenesis bioassay in mouse liver provides evidence for a carcinogenic mechanism devoid of human relevance: the dalcetrapib experience. | 2012 Mar 15 |
Patents
Sample Use Guides
Human liver microsomes and a panel of substrates for CYP enzymes were used to determine IC(50) for inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 by dalcetrapib. Drug was inhibitory to all CYP enzymes tested. IC(50) values ranged from 1.5 +/- 0.1 uM for CYP2C8 to 82 +/- 4 uM for CYP2D6.
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211513-21-2
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6918816
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PEW5P6H57S
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DTXSID10426090
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PRODRUG (METABOLITE ACTIVE)
