Apabetalone
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| Names | |
|---|---|
| IUPAC name
2-[4-(2-Hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-4(3H)-quinazolinone
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| Other names
RVX208, RVX-208
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| Identifiers | |
3D model (
JSmol ) |
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| ChEMBL | |
| ChemSpider | |
| DrugBank | |
ECHA InfoCard
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100.242.963 |
| EC Number |
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| KEGG | |
PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| Properties | |
| C20H22N2O5 | |
| Molar mass | 370.405 g·mol−1 |
| Density | 1.3±0.1 g/cm3 |
| Hazards | |
| GHS labelling: | |
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| Warning | |
| H371 | |
| P260, P264, P270, P309+P311, P405, P501 | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Apabetalone (development codes RVX 208, RVX-208, and RVX000222)diabetes mellitus. In a short-term study in prediabetics, favorable changes in glucose metabolism were observed in patients receiving apabetalone.[7] An international, multicenter phase III trial, “Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Mellitus Subjects with Coronary Artery Disease” (BETonMACE) commenced in October 2015.[8] The trial is designed to determine whether apabetalone in combination with statins can decrease cardiac events compared to treatment with statins alone.
Mechanism of action
The molecular targets of apabetalone are
transcription via an epigenetic mechanism. Apabetalone selectively binds to the second bromodomain (BD2). When apabetalone binds to BRD4, it impacts key biological processes that contribute to CVD such as cholesterol levels and inflammation.[12]
Apabetalone stimulates
atherosclerotic plaque in arteries to liver for excretion via the reverse cholesterol transport (RCT) pathway. This process is thought to stabilize the plaque to avoid coronary events. Clinical trials have shown apabetalone increases ApoA-I and HDL.[12] Further, serum from individuals taking apabetalone had increased cholesterol efflux capacity, indicating the HDL generated in response to apabetalone functions in RCT.[13]
clinical trials, more favorable effects of apabetalone on coronary disease progression have been observed in patients with elevated levels of inflammatory markers.[14] Apabetalone was also reported to reduce inflammation in pre-clinical models.[15] Subsequent research showed apabetalone targets multiple processes that underlie CVD.[12] The impact on any of these pathways, independently or cumulatively, may contribute to the lower incidence of MACE observed in clinical trials
.
References
- ^ E. McNeill, RVX-208, a stimulator of apolipoprotein AI gene expression for the treatment of cardiovascular diseases, Current opinion in investigational drugs, 11 (2010) 357-364.
- ^ "Home - Resverlogix Corp".
- S2CID 24927630.
- PMID 21255957.
- ^ S.J. Nicholls, R. Puri, K. Wolski, C.M. Ballantyne, P.J. Barter, H.B. Brewer, J.J.P. Kastelein, B. Hu, K. Uno, Y. Kataoka, J-P. R. Herrman, B. Merkely, M. Borgman, S.E. Nissen. Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial, Am J Cardioovascular Drugs, 16 (2016) 55-65.
- ^ J. Johansson, A. Gordon, C. Halliday, N.C. Wong, Effects of RVX-208 on major adverse cardiac events (MACE), apolipoprotein A-I and High-Density-Lipoproteins; A post-hoc analysis from the pooled SUSTAIN and ASSURE clinical trials (Congress abstract), Eur Heart J Suppl, 35 (2014) 723-724.
- PMID 27173469.
- ^ "www.clinicaltrials.gov". 20 August 2020.
- ^ PMID 24391744.
- PMID 24248379.
- PMID 22464331.
- ^ PMID 26868508.
- ^ PMID 20513599.
- ^ R. Puri, Y. Kataoka, K. Wolski, A. Gordon, J. Johansson, N.C. Wong, S. Nissen, S. Nicholls, Effects of an apolipoprotein A-1 inducer on progression of coronary atherosclerosis and cardiovascular events in patients with elevated inflammatory markers, Journal of the American College of Cardiology, 63 (2014) S0735-1097
- PMID 25016363.