Apabetalone

Last updated
Apabetalone
RVX-208.svg
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 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 12-112-4
KEGG
PubChem CID
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:
GHS-pictogram-silhouette.svg
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).

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.

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 .

Related Research Articles

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle. HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL has been associated with the progression of atherosclerosis.

<span class="mw-page-title-main">Atherosclerosis</span> Inflammatory disease involving buildup of lesions in the walls of arteries

Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types, and driven by elevated levels of cholesterol in the blood. These lesions may lead to narrowing of the arterial walls due to buildup of atheromatous plaques. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. In severe cases, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney disorders, depending on which body part(s) the affected arteries are located in the body.

Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases, which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for cardiovascular disease, abnormal levels do not mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia.

Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Phytosterol</span> Class of steroids derived from plants

Phytosterols are phytosteroids, similar to cholesterol, that serve as structural components of biological membranes of plants. They encompass plant sterols and stanols. More than 250 sterols and related compounds have been identified. Free phytosterols extracted from oils are insoluble in water, relatively insoluble in oil, and soluble in alcohols.

<span class="mw-page-title-main">Cholesteryl ester transfer protein</span> Mammalian protein found in Homo sapiens

Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density lipoproteins (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.

A CETP inhibitor is a member of a class of drugs that inhibit cholesterylester transfer protein (CETP). They are intended to reduce the risk of atherosclerosis by improving blood lipid levels. At least three medications within this class have failed to demonstrate a beneficial effect.

<span class="mw-page-title-main">ApoA-I Milano</span>

Apolipoprotein A-I Milano is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease. ApoA-I Milano was first identified by Dr. Cesare Sirtori in Milan, who also demonstrated that its presence significantly reduced cardiovascular disease, even though it caused a reduction in HDL levels and an increase in triglyceride levels.

The lipid hypothesis is a medical theory postulating a link between blood cholesterol levels and the occurrence of cardiovascular disease. A summary from 1976 described it as: "measures used to lower the plasma lipids in patients with hyperlipidemia will lead to reductions in new events of coronary heart disease". It states, more concisely, that "decreasing blood cholesterol [...] significantly reduces coronary heart disease".

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

<span class="mw-page-title-main">Lipoprotein(a)</span> Low-density lipoprotein containing apolipoprotein(a)

Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.

<span class="mw-page-title-main">Apolipoprotein AI</span> Protein used in lipid metabolism

Apolipoprotein AI(Apo-AI) is a protein that in humans is encoded by the APOA1 gene. As the major component of HDL particles, it has a specific role in lipid metabolism.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Familial dysbetalipoproteinemia</span> Medical condition

Familial dysbetalipoproteinemia or type III hyperlipoproteinemia is a condition characterized by increased total cholesterol and triglyceride levels, and decreased HDL levels.

Steven E. Nissen is an American cardiologist, researcher and patient advocate. He was chairman of cardiovascular medicine at the Cleveland Clinic, in Cleveland, Ohio.

<span class="mw-page-title-main">Varespladib</span> Chemical compound

Varespladib is an inhibitor of the IIa, V, and X isoforms of secretory phospholipase A2 (sPLA2). The molecule acts as an anti-inflammatory agent by disrupting the first step of the arachidonic acid pathway of inflammation. From 2006 to 2012, varespladib was under active investigation by Anthera Pharmaceuticals as a potential therapy for several inflammatory diseases, including acute coronary syndrome and acute chest syndrome. The trial was halted in March 2012 due to inadequate efficacy. The selective sPLA2 inhibitor varespladib (IC50 value 0.009 μM in chromogenic assay, mole fraction 7.3X10-6) was studied in the VISTA-16 randomized clinical trial (clinicaltrials.gov Identifier: NCT01130246) and the results were published in 2014. The sPLA2 inhibition by varespladib in this setting seemed to be potentially harmful, and thus not a useful strategy for reducing adverse cardiovascular outcomes from acute coronary syndrome. Since 2016, scientific research has focused on the use of Varespladib as an inhibitor of snake venom toxins using various types of in vitro and in vivo models. Varespladib showed a significant inhibitory effect to snake venom PLA2 which makes it a potential first-line drug candidate in snakebite envenomation therapy. In 2019, the U.S. Food and Drug Administration (FDA) granted varespladib orphan drug status for its potential to treat snakebite.

The vertical auto profile (VAP) test is a cholesterol, lipid and lipoprotein test.

Major adverse cardiovascular events is a composite endpoint frequently used in cardiovascular research. Despite widespread use of the term in clinical trials, the definitions of MACE can differ, which makes comparison of similar studies difficult.

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 randomized 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. 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. 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. 1 2 3 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. 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 . 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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