Chemistry:Varespladib

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Short description: Chemical compound
Varespladib
Varespladib.svg
Clinical data
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Legal status
Legal status
  • investigational
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CAS Number
PubChem CID
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UNII
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Chemical and physical data
FormulaC21H20N2O5
Molar mass380.400 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)

Varespladib is an inhibitor of the IIa, V, and X isoforms of secretory phospholipase A2 (sPLA2).[1][2][3] The molecule acts as an anti-inflammatory agent by disrupting the first step of the arachidonic acid pathway of inflammation.[4] 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.[5][6] The trial was halted in March 2012 due to inadequate efficacy.[7] The selective sPLA2 inhibitor varespladib (IC50 value 0.009 μM in chromogenic assay, mole fraction 7.3X10-6)[8] was studied in the VISTA-16 randomized clinical trial (clinicaltrials.gov Identifier: NCT01130246) and the results were published in 2014.[8] 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[9][10][11][12][13] 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.

History

Varespladib methyl was originally developed jointly by Eli Lilly and Company and Shionogi & Co., Ltd., and was acquired by Anthera Pharmaceuticals in 2006.[14]

A Phase II study demonstrated selective sPLA2 inhibition as well as statistically significant anti-inflammatory responses and reductions in LDL cholesterol levels.[15] Two other Phase II trials, conducted in patients with coronary artery disease, found significant decreases in sPLA2 and LDL cholesterol levels, as well as C-reactive protein (CRP) and other inflammatory biomarkers.[16][17][18] Varespladib methyl has also been shown to further reduce LDL and inflammatory biomarker levels when administered in conjunction with a cholesterol lowering statin therapy.[19]

In 2010, a Phase III study entitled VISTA-16 was initiated to evaluate the safety and efficacy of short-term treatment with varespladib methyl in subjects with ACS.[20] The trial was halted in March 2012 due to insufficient efficacy.[21] On November 18, 2013, an excess of myocardial infarctions, and of the composite endpoint of cardiovascular mortality, myocardial infarctions and stroke in the VISTA-16 study were reported.[8]

First report on its efficacy as an antidote for snake venoms comes from 2016.[13] Due to oral bioavailability it is considered as a potential first-line field-treatment for snakebite envenomation, which could be applied before provision of definitive medical care.[22]

Oral varespladib

Varespladib methyl
Varespladib methyl.svg
Clinical data
Other namesA-002
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administration		Oral
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Legal status
  • Investigational
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UNII
Chemical and physical data
FormulaC22H22N2O5
Molar mass394.427 g·mol−1
3D model (JSmol)
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Varespladib methyl (also known as A-002, formerly LY333013 and S-3013) is a secretory phospholipase A2 (sPLA2) inhibitor formerly under development by Anthera Pharmaceuticals as a treatment for acute coronary syndrome (ACS).[23] Varespladib methyl is an orally bioavailable prodrug of the molecule varespladib.[24] From 2006 to 2012, varespladib methyl was under active investigation by Anthera Pharmaceuticals as a potential therapy for several inflammatory diseases, including acute coronary syndrome.[25][26] In March 2012, Anthera halted further investigation of varespladib per a recommendation from an independent Data Safety Monitoring Board.[25] Varespladib and varespladib methyl were characterised as effective molecules in neutralization of snakes venoms[27] and are under experimental evaluation.[28]

Intravenous varespladib

Varespladib sodium
Varespladib sodium.svg
Clinical data
Other namesA-001
Pregnancy
category
  • —
Routes of
administration		IV
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC21H19N2NaO5
Molar mass402.382 g·mol−1
3D model (JSmol)

Varespladib sodium (also known as A-001, previously LY315920 and S-5920) is a sodium salt of varespladib designed for intravenous delivery.[29] It was under evaluation by Anthera Pharmaceuticals as an anti-inflammatory sPLA2 inhibitor for the prevention of acute chest syndrome (ACS), the leading cause of death for patients with sickle-cell disease.[5]

Elevated serum levels of sPLA2 have been observed in sickle-cell patients preceding and during ACS episodes. This profound elevation in sPLA2 levels is not observed in sickle-cell patients at steady-state or during a vaso-occlusive crisis, or in patients with respiratory diseases such as pneumonia.[30][31] A reduction in serum sPLA2 levels, for example through blood transfusion, reduces the risk of an ACS, suggesting that sPLA2 plays an important role in the onset of ACS.[32]

Anthera Pharmaceuticals acquired varespladib sodium from Lilly and Shionogi in 2006.[5] In 2007, the U.S. Food and Drug Administration (FDA) granted varespladib sodium orphan drug status for its potential to treat patients with sickle-cell disease, which was later withdrawn.[33] In 2009, Anthera Pharmaceuticals completed a Phase II study of varespladib sodium in subjects with sickle cell disease at risk for ACS.[34]

Inhibitory effect on snake venoms

Snakebite envenomation can cause local tissue damage, with edema, hemorrhage, myonecrosis, and systemic toxic responses, including organ failure. In an early report on inhibition of snake venom toxicities, Varespladib, and its orally bioavailable prodrug methyl-varespladib (LY333013) showed strong inhibition of 28 types of svPLA2s from six continents.[13] Varespladib treatment exerted a significant inhibitory effect on snake venom PLA2 both in vitro and in vivo. Hemorrhage and myonecrosis initiated by D. acuts, A. halys, N. atra, and B. multicinctus in an animal model were significantly reversed by varespladib. Furthermore, edema in gastrocnemius muscle was also attenuated.[12] The sPLA2 inhibitor, LY315920 (varespladib sodium), and its orally bioavailable prodrug, LY333013 (varespladib methyl) were highly effective in preventing lethality following experimental envenoming by M. fulvius in a porcine animal model.[10]

Considering that some of the toxins of snake venoms are enzymes, the search for low molecular weight enzyme inhibitors that could be safely administered immediately after a snakebite re-focused scientists' attention on Varespladib. Its ability to neutralize the enzymatic and toxic activities of three isolated PLA2 toxins (from medically important snakes found in different region around the world) of structural groups I (pseudexin) and II (crotoxin B and myotoxin I) was evaluated. The results obtained showed that Varespladib was able to neutralize the in vitro cytotoxic and in vivo myotoxic activities of purified PLA2s of both the structural group I (pseudexin) and II (myotoxin-I and crotoxin B), however further detailed analysis are needed.[11] Varespladib also effectively inhibited the non-enzymatic myotoxic activity of the snake venom PLA2-like protein (MjTX-II). Co-crystallization of Varespladib with MjTX-II toxin revealed that the compound binds to a hydrophobic channel of the protein. Such interaction blocks fatty acids binding, thus inhibiting allosteric activation of the toxin. This leads to the toxin losing its ability to disrupt cell membranes. [9]

In 2019, the U.S. Food and Drug Administration (FDA) granted varespladib orphan drug status for its potential to treat snakebite.[35]

Mechanism

Prodrug activation

Varespladib methyl, in contrast to varespladib, is orally bioavailable and after absorption from the GI tract, it undergoes rapid ester hydrolysis to the active molecule – varespladib.[36]

sPLA2 inhibition

Increased levels of sPLA2 have been observed in patients with cardiovascular disease, and may lead to both acute and chronic disease manifestations by promoting vascular inflammation. Plasma levels of sPLA2 can predict coronary events in patients who recently suffered an ACS as well as in those with stable coronary artery disease.[37][38]

Furthermore, sPLA2 remodels lipoproteins, notably low-density lipoproteins (LDL) and their receptors, which are responsible for removing cholesterol from the body. This remodeling can lead to increased deposition of LDL and cholesterol in the artery wall. In combination with chronic vascular inflammation, these deposits lead to atherosclerosis.[39]

Varespladib inhibits the IIA, V and X isoforms of sPLA2 to reduce inflammation, lower and modulate lipid levels, and reduce levels of C-reactive protein (CRP) and interleukin-6 (IL-6), both indicators of inflammation.[23][16]

Snake venom antidote activity

sPLA2 is also present in snake venoms and implicated in their toxicity. It plays a role in the morbidity and mortality from snakebite envenomations, triggering induced cell lysis, disrupted hemostasis, and diminished oxygen transport, as well as myotoxicity and neurotoxicity which can lead to paralysis.[27]

Varespladib methyl, as well as varespladib, were found to be inhibitors of the sPLA2 of snake venoms. Varespladib methyl was less potent than varespladib. Both showed activity against a broad spectrum of different snake venoms originating from six continents.[13] They protected rodents against neurotoxicity and hemostatic toxicity, increasing survival of envenomed animals.[10][28]

Varespladib also effectively inhibited in vitro and in vivo the non-enzymatic myotoxic activity of snake venom's PLA2-like protein (MjTX-II). Co-crystallization of varespladib with MjTX-II toxin (PDB code: 6PWH[40]) revealed that the drug binds to a hydrophobic channel of the protein. This blocks fatty acids from binding there, thus inhibiting their allosteric activation of the toxin, thereby impairing its ability to disrupt cell membranes.[41]

References

  1. ↑ "Following Encouraging Results, Anthera to Continue IMACTS Trial for the Prevention of Acute Chest Syndrome in Patients with Sickle Cell Disease" (Press release). Anthera Pharmaceuticals, Inc. 24 March 2009.
  2. ↑ "A-002: Short Term (16 week) Treatment of Acute Coronary Syndrome.". Anthera Pharmaceuticals.. http://www.anthera.com/products_a002.asp. 
  3. ↑ "Varespladib". American Journal of Cardiovascular Drugs 11 (2): 137–143. April 2011. doi:10.2165/11533650-000000000-00000. PMID 21446779. 
  4. ↑ Medical Biochemistry (2 ed.). Elsevier Mosby. 2005. pp. 555. ISBN 0-7234-3341-0. https://archive.org/details/medicalbiochemis0000unse/page/555. 
  5. ↑ 5.0 5.1 5.2 "Anthera Licenses Portfolio of Anti-Inflammatory Products From Eli Lilly and Company and Shionogi & Co., Ltd" (Press release). Anthera Pharmaceuticals, Inc. 6 September 2006.
  6. ↑ "Science: sPLA2". Anthera Pharmaceuticals. http://www.anthera.com/science_spla2.asp. 
  7. ↑ Clinical trial number NCT01130246 for "VISTA-16 Trial: Evaluation of Safety and Efficacy of Short-term A-002 Treatment in Subjects With Acute Coronary Syndrome" at ClinicalTrials.gov
  8. ↑ 8.0 8.1 8.2 "Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial". JAMA 311 (3): 252–262. January 2014. doi:10.1001/jama.2013.282836. PMID 24247616. 
  9. ↑ 9.0 9.1 "Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920)". Scientific Reports 9 (1): 17203. November 2019. doi:10.1038/s41598-019-53755-5. PMID 31748642. Bibcode: 2019NatSR...917203S. 
  10. ↑ 10.0 10.1 10.2 "Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom". Toxins 10 (11): 479. November 2018. doi:10.3390/toxins10110479. PMID 30453607. 
  11. ↑ 11.0 11.1 "Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A2". Toxicon 157: 1–7. January 2019. doi:10.1016/j.toxicon.2018.11.292. PMID 30447275. 
  12. ↑ 12.0 12.1 "Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation". Molecules 23 (2): 391. February 2018. doi:10.3390/molecules23020391. PMID 29439513. 
  13. ↑ 13.0 13.1 13.2 13.3 "Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation". Toxins 8 (9): 248. August 2016. doi:10.3390/toxins8090248. PMID 27571102. 
  14. ↑ "Anthera Licenses Portfolio of Anti-Inflammatory Products From Eli Lilly and Company and Shionogi & Co., Ltd" (Press release). Anthera Pharmaceuticals, Inc. 6 September 2006.
  15. ↑ "Anthera's Varespladib Meets Primary Endpoint In Phase 2 Francis Trial For The Treatment Of Acute Coronary Syndrome" (Press release). Anthera Pharmaceuticals, Inc. 6 May 2009.
  16. ↑ 16.0 16.1 "Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease". European Heart Journal 32 (8): 999–1005. April 2011. doi:10.1093/eurheartj/ehq374. PMID 21081550. 
  17. ↑ "Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial". Lancet 373 (9664): 649–658. February 2009. doi:10.1016/S0140-6736(09)60403-7. PMID 19231633. 
  18. ↑ "Varespladib methyl in cardiovascular disease". Expert Opinion on Investigational Drugs 19 (10): 1245–1255. October 2010. doi:10.1517/13543784.2010.517193. PMID 20809869. 
  19. ↑ "Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients". Journal of the American College of Cardiology 56 (14): 1079–1088. September 2010. doi:10.1016/j.jacc.2010.06.015. PMID 20863951. 
  20. ↑ "Anthera Enrolls First Patients in Pivotal Varespladib Phase 3 Clinical Study" (Press release). Anthera Pharmaceuticals, Inc. 23 June 2010.
  21. ↑ Clinical trial number NCT01130246 for "VISTA-16 Trial: Evaluation of Safety and Efficacy of Short-term A-002 Treatment in Subjects With Acute Coronary Syndrome." at ClinicalTrials.gov
  22. ↑ "Strategy for a globally coordinated response to a priority neglected tropical disease: Snakebite envenoming". PLOS Neglected Tropical Diseases 13 (2): e0007059. February 2019. doi:10.1371/journal.pntd.0007059. PMID 30789906. 
  23. ↑ 23.0 23.1 "A-002: Short Term (16 week) Treatment of Acute Coronary Syndrome". Anthera Pharmaceuticals, Inc.. http://www.anthera.com/products_a002.asp/. 
  24. ↑ "Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE-/- mice". Journal of Cardiovascular Pharmacology 53 (1): 60–65. January 2009. doi:10.1097/FJC.0b013e318195bfbc. PMID 19129734. 
  25. ↑ 25.0 25.1 "Anthera Licenses Portfolio of Anti-Inflammatory Products From Eli Lilly and Company and Shionogi & Co., Ltd" (Press release). Anthera Pharmaceuticals, Inc. 6 September 2006.
  26. ↑ "Science: sPLA2". Anthera Pharmaceuticals. http://www.anthera.com/science_spla2.asp. 
  27. ↑ 27.0 27.1 "Snake Venom PLA2, a Promising Target for Broad-Spectrum Antivenom Drug Development". BioMed Research International 2017: 6592820. 2017. doi:10.1155/2017/6592820. PMID 29318152. 
  28. ↑ 28.0 28.1 "Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms". Toxins 12 (2): 131. February 2020. doi:10.3390/toxins12020131. PMID 32093386. 
  29. ↑ "A-001: Prevention of Acute Chest Syndrome in Sickle Cell Disease.". Anthera Pharmaceuticals.. http://www.anthera.com/products_a001.asp. 
  30. ↑ "Phospholipase A2 levels in acute chest syndrome of sickle cell disease". Blood 87 (6): 2573–2578. March 1996. doi:10.1182/blood.V87.6.2573.bloodjournal8762573. PMID 8630425. 
  31. ↑ "Secretory phospholipase A(2) predicts impending acute chest syndrome in sickle cell disease". Blood 96 (9): 3276–3278. November 2000. doi:10.1182/blood.V96.9.3276. PMID 11050014. 
  32. ↑ "Group v secretory phospholipase A2 promotes atherosclerosis: evidence from genetically altered mice". Arteriosclerosis, Thrombosis, and Vascular Biology 27 (3): 600–606. March 2007. doi:10.1161/01.ATV.0000257133.60884.44. PMID 17204667. 
  33. ↑ "Anthera's A-001 Receives Orphan Drug Status For The Prevention Of Acute Chest Syndrome In Patients With Sickle Cell Disease" (Press release). Anthera Pharmaceuticals, Inc. 18 December 2007.
  34. ↑ ClinicalTrials.gov.. "IMPACTS Trial: Investigation of the Modulation of Phospholipase in Acute Chest Syndrome.". United States National Institute of Health.. http://clinicaltrials.gov/ct2/show/NCT00434473. 
  35. ↑ "Search Orphan Drug Designations and Approvals". https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm. 
  36. ↑ "Varespladib methyl, an oral phospholipase A2 inhibitor for the potential treatment of coronary artery disease". IDrugs 12 (9): 585–592. September 2009. PMID 19697278. 
  37. ↑ "Circulating secretory phospholipase A2 activity predicts recurrent events in patients with severe acute coronary syndromes". Journal of the American College of Cardiology 46 (7): 1249–1257. October 2005. doi:10.1016/j.jacc.2005.06.056. PMID 16198839. 
  38. ↑ "Circulating levels of secretory type II phospholipase A(2) predict coronary events in patients with coronary artery disease". Circulation 100 (12): 1280–1284. September 1999. doi:10.1161/01.CIR.100.12.1280. PMID 10491371. 
  39. ↑ "Lipoprotein-associated and secreted phospholipases A₂ in cardiovascular disease: roles as biological effectors and biomarkers". Circulation 122 (21): 2183–2200. November 2010. doi:10.1161/CIRCULATIONAHA.110.936393. PMID 21098459. 
  40. ↑ "RCSB PDB - 6PWH: Cystal structure of Myotoxin II from Bothrops moojeni co-crystallized with Varespladib (LY315920)" (in en-US). RCSB Protein Data Bank. https://www.rcsb.org/structure/6PWH. 
  41. ↑ "Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920)". Scientific Reports 9 (1): 17203. November 2019. doi:10.1038/s41598-019-53755-5. PMID 31748642. Bibcode: 2019NatSR...917203S. 

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