Apabetalone

Apabetalone (development codes RVX 208, RVX-208, and RVX000222)[1] is an orally available small molecule created by Resverlogix Corp.[2] that is being evaluated in clinical trials for the treatment of atherosclerosis and associated cardiovascular disease (CVD).[3][4] In the phase II clinical trial ASSURE in patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels, apabetalone showed no greater increase in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels or incremental regression of atherosclerosis than administration of placebo, while causing a statistically significant greater incidence of elevated liver enzymes.[5] However, pooled analysis of the effect of apabetalone in three phase II clinical trials ASSERT, ASSURE, and SUSTAIN demonstrated increases in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels, as well as decreases in the incidence of major adverse cardiac events (MACE).[6] Reduction of MACE was more profound in patients with 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.

Apabetalone
Names
IUPAC name
2-[4-(2-Hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-4(3H)-quinazolinone
Other names
RVX208, RVX-208
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.242.963
EC Number
  • 12-112-4
KEGG
UNII
  • InChI=1S/C20H22N2O5/c1-11-7-13(8-12(2)18(11)27-6-5-23)19-21-15-9-14(25-3)10-16(26-4)17(15)20(24)22-19/h7-10,23H,5-6H2,1-4H3,(H,21,22,24)
    Key: NETXMUIMUZJUTB-UHFFFAOYSA-N
  • CC1=CC(=CC(=C1OCCO)C)C2=NC3=C(C(=CC(=C3)OC)OC)C(=O)N2
Properties
C20H22N2O5
Molar mass 370.405 g·mol−1
Density 1.3±0.1 g/cm3
Hazards
GHS labelling:
GHS08: Health hazard
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).
Infobox references

Mechanism of action

The molecular targets of apabetalone are bromodomain and extra terminal domain (BET) proteins, and in particular the BET family member BRD4.[9][10] BET proteins, which contain two bromodomains,[11] interact with acetylated lysines on histones bound to DNA to regulate gene 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 ApoA-I gene expression and production of the protein.[9][13] ApoA-I is the main protein component of high-density lipoprotein (HDL), which can transfer cholesterol from 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]

Inflammation is also a major contributor to atherosclerosis and CVD. Both ApoA-I induction and anti-inflammatory effects are common properties of BET inhibitors. In 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
  1. 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.
  2. "Home - Resverlogix Corp".
  3. Nicholls, Stephen J.; Gordon, Allan; Johannson, Jan; Ballantyne, Christie M.; Barter, Philip J.; Brewer, H. Bryan; Kastelein, John J. P.; Wong, Norman C.; Borgman, Marilyn R. N.; Nissen, Steven E. (17 February 2012). "ApoA-I Induction as a Potential Cardioprotective Strategy: Rationale for the SUSTAIN and ASSURE Studies". Cardiovascular Drugs and Therapy. 26 (2): 181–187. doi:10.1007/s10557-012-6373-5. PMID 22349989. S2CID 24927630.
  4. Nicholls, Stephen J.; Gordon, Allan; Johansson, Jan; Wolski, Kathy; Ballantyne, Christie M.; Kastelein, John J.P.; Taylor, Allen; Borgman, Marilyn; Nissen, Steven E. (March 2011). "Efficacy and Safety of a Novel Oral Inducer of Apolipoprotein A-I Synthesis in Statin-Treated Patients With Stable Coronary Artery Disease". Journal of the American College of Cardiology. 57 (9): 1111–1119. doi:10.1016/j.jacc.2010.11.015. PMID 21255957.
  5. 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.
  6. 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.
  7. Siebel, Andrew L.; Trinh, Si Khiang; Formosa, Melissa F.; Mundra, Piyushkumar A.; Natoli, Alaina K.; Reddy-luthmoodoo, Medini; Huynh, Kevin; Khan, Anmar A.; Carey, Andrew L. (2016-06-01). "Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomize,ref.ed controlled trial". Metabolism. 65 (6): 904–914. doi:10.1016/j.metabol.2016.03.002. ISSN 0026-0495. PMID 27173469.
  8. "www.clinicaltrials.gov". 20 August 2020.
  9. McLure, Kevin G.; Gesner, Emily M.; Tsujikawa, Laura; Kharenko, Olesya A.; Attwell, Sarah; Campeau, Eric; Wasiak, Sylwia; Stein, Adam; White, Andre; Fontano, Eric; Suto, Robert K.; Wong, Norman C. W.; Wagner, Gregory S.; Hansen, Henrik C.; Young, Peter R.; Vertessy, Beata G. (31 December 2013). "RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist". PLOS ONE. 8 (12): e83190. Bibcode:2013PLoSO...883190M. doi:10.1371/journal.pone.0083190. PMC 3877016. PMID 24391744.
  10. Picaud, S.; Wells, C.; Felletar, I.; Brotherton, D.; Martin, S.; Savitsky, P.; Diez-Dacal, B.; Philpott, M.; Bountra, C.; Lingard, H.; Fedorov, O.; Muller, S.; Brennan, P. E.; Knapp, S.; Filippakopoulos, P. (18 November 2013). "RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain". Proceedings of the National Academy of Sciences. 110 (49): 19754–19759. Bibcode:2013PNAS..11019754P. doi:10.1073/pnas.1310658110. PMC 3856850. PMID 24248379.
  11. Filippakopoulos, Panagis; Picaud, Sarah; Mangos, Maria; Keates, Tracy; Lambert, Jean-Philippe; Barsyte-Lovejoy, Dalia; Felletar, Ildiko; Volkmer, Rudolf; Müller, Susanne; Pawson, Tony; Gingras, Anne-Claude; Arrowsmith, Cheryl H.; Knapp, Stefan (March 2012). "Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family". Cell. 149 (1): 214–231. doi:10.1016/j.cell.2012.02.013. PMC 3326523. PMID 22464331.
  12. Gilham, Dean; Wasiak, Sylwia; Tsujikawa, Laura M.; Halliday, Christopher; Norek, Karen; Patel, Reena G.; Kulikowski, Ewelina; Johansson, Jan; Sweeney, Michael (2016-04-01). "RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease". Atherosclerosis. 247: 48–57. doi:10.1016/j.atherosclerosis.2016.01.036. ISSN 0021-9150. PMID 26868508.
  13. Bailey, Dana; Jahagirdar, Ravi; Gordon, Allan; Hafiane, Anouar; Campbell, Steven; Chatur, Safia; Wagner, Gregory S.; Hansen, Henrik C.; Chiacchia, Fabrizio S.; Johansson, Jan; Krimbou, Larbi; Wong, Norman C.W.; Genest, Jacques (June 2010). "RVX-208". Journal of the American College of Cardiology. 55 (23): 2580–2589. doi:10.1016/j.jacc.2010.02.035. PMID 20513599.
  14. 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
  15. Jahagirdar, Ravi; Zhang, Haiyan; Azhar, Salman; Tobin, Jennifer; Attwell, Sarah; Yu, Raymond; Wu, Jin; McLure, Kevin G.; Hansen, Henrik C. (2014-09-01). "A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice". Atherosclerosis. 236 (1): 91–100. doi:10.1016/j.atherosclerosis.2014.06.008. ISSN 0021-9150. PMID 25016363.
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