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 interactive 3D Image
Properties
C20H22N2O5
Molar mass 370.41 g·mol−1
Density 1.3±0.1 g/cm3
Except where otherwise noted, data are 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

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 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 such as cholesterol levels and inflammation.
RVX-208 stimulates ApoA-I gene expression and production of the protein.[6][9] 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 RVX-208 increases ApoA-I and HDL. Further, serum from individuals taking RVX-208 had increased cholesterol efflux capacity, indicating the HDL generated in response to RVX-208 functions in RCT.[9]

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 RVX-208 on coronary disease progression have been observed in patients with elevated levels of inflammatory markers.[10]

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 (Congress abstract), Eur Heart J Suppl, 35 (2014) 723-724.
  6. 1 2 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. PMID 24391744.
  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. 1 2 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. ↑ 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


This article is issued from Wikipedia - version of the Friday, January 15, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.