Chemistry:RVX 208

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RVX 208 (also known as RVX-208, RVX000222 or apabetalone)[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, apabetalone 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 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.[6] 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.[7] 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 bromodomain and extra terminal domain (BET) proteins, and in particular the BET family member BRD4.[8][9] BET proteins, which contain two bromodomains,[10] 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.[11]
Apabetalone stimulates ApoA-I gene expression and production of the protein.[8][12] 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.[11] Further, serum from individuals taking apabetalone had increased cholesterol efflux capacity, indicating the HDL generated in response to apabetalone functions in RCT.[12]

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.[13] Apabetalone was also reported to reduce inflammation in pre-clinical models.[14] Subsequent research showed apabetalone targets multiple processes that underlie CVD.[11] 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. ↑ 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. et al. (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 et al. (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. ↑ 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. ↑ Siebel, Andrew L.; Trinh, Si Khiang; Formosa, Melissa F.; Mundra, Piyushkumar A.; Natoli, Alaina K.; Reddy-luthmoodoo, Medini; Huynh, Kevin; Khan, Anmar A. et al. (2016-06-01). "Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial" (in English). Metabolism 65 (6): 904–914. doi:10.1016/j.metabol.2016.03.002. ISSN 0026-0495. http://linkinghub.elsevier.com/retrieve/pii/S0026049516000561. 
  7. ↑ "www.clinicaltrials.gov". https://clinicaltrials.gov/ct2/show/NCT02586155?term=apabetalone&rank=1. 
  8. ↑ 8.0 8.1 McLure, Kevin G.; Gesner, Emily M.; Tsujikawa, Laura; Kharenko, Olesya A.; Attwell, Sarah; Campeau, Eric; Wasiak, Sylwia; Stein, Adam et al. (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. 
  9. ↑ Picaud, S.; Wells, C.; Felletar, I.; Brotherton, D.; Martin, S.; Savitsky, P.; Diez-Dacal, B.; Philpott, M. et al. (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. PMID 24248379. 
  10. ↑ Filippakopoulos, Panagis; Picaud, Sarah; Mangos, Maria; Keates, Tracy; Lambert, Jean-Philippe; Barsyte-Lovejoy, Dalia; Felletar, Ildiko; Volkmer, Rudolf et al. (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. PMID 22464331. 
  11. ↑ 11.0 11.1 11.2 Gilham, Dean; Wasiak, Sylwia; Tsujikawa, Laura M.; Halliday, Christopher; Norek, Karen; Patel, Reena G.; Kulikowski, Ewelina; Johansson, Jan et al. (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" (in English). Atherosclerosis 247: 48–57. doi:10.1016/j.atherosclerosis.2016.01.036. ISSN 0021-9150. http://linkinghub.elsevier.com/retrieve/pii/S0021915016300351. 
  12. ↑ 12.0 12.1 Bailey, Dana; Jahagirdar, Ravi; Gordon, Allan; Hafiane, Anouar; Campbell, Steven; Chatur, Safia; Wagner, Gregory S.; Hansen, Henrik C. et al. (June 2010). "RVX-208". Journal of the American College of Cardiology 55 (23): 2580–2589. doi:10.1016/j.jacc.2010.02.035. 
  13. ↑ 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
  14. ↑ Jahagirdar, Ravi; Zhang, Haiyan; Azhar, Salman; Tobin, Jennifer; Attwell, Sarah; Yu, Raymond; Wu, Jin; McLure, Kevin G. et al. (2014-09-01). "A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice" (in English). Atherosclerosis 236 (1): 91–100. doi:10.1016/j.atherosclerosis.2014.06.008. ISSN 0021-9150. PMID 25016363. http://linkinghub.elsevier.com/retrieve/pii/S0021915014012386. 




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