RVX 208

RVX 208
Names
IUPAC name
2-[4-(2-Hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-4(3H)-quinazolinone
Other names
RVX208,RVX-208
Identifiers
1044870-39-4
Jmol-3D images Image
Properties
Molecular formula
 C20H22N2O5
Molar mass 370.40 g·mol−1
Density 1.3±0.1 g/cm3
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

RVX 208 (RVX-208)[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 two phase II clinical trials in patients with established CVD, RVX-208 increased HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels, as well as decreased the incidence of major adverse cardiac events (MACE).[5] Reduction of MACE was accentuated in patients with diabetes mellitus.

Mechanism of action

RVX-208 acts via an epigenetic mechanism. The molecular targets of RVX-208 are bromodomain and extra terminal domain (BET) proteins, and in particular the BET family member BRD4.[6][7] BET proteins, which contain two bromodomains,[8] interact with acetylated lysines such as those on histones bound to DNA to regulate gene transcription. RVX-208 selectively binds to the second bromodomain (BD2). When RVX-208 binds to BRD4, it impacts key biological processes that contribute to CVD. RVX-208 stimulates ApoA-I gene expression and production of the protein.[9][10] 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. In a phase 1 clinical trial, serum from healthy volunteers taking RVX-208 had increased cholesterol efflux capacity, indicating the HDL generated in response to RVX-208 participates in RCT.[11]

Besides ApoA-I, RVX-208 also increases serum HDL-c levels in primates through RCT.[12]

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. ↑ http://www.resverlogix.com/
  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.
  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.
  5. ↑ 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, Eur Heart J Suppl, 35 (2014) 732-724.
  6. ↑ 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. doi:10.1371/journal.pone.0083190.
  7. ↑ 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. doi:10.1073/pnas.1310658110.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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. doi:10.1371/journal.pone.0083190.
  11. ↑ 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.
  12. ↑ D. Bailey, R. Jahagirdar, A. Gordon, A. Hafiane, S. Campbell, S. Chatur, G.S. Wagner, H.C. Hansen, F.S. Chiacchia, J. Johansson, L. Krimbou, N.C. Wong, J. Genest, RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo, Journal of the American College of Cardiology, 55 (2010) 2580-2589.