varespladib

Varespladib methyl was originally developed jointly by Eli Lilly and Company and Shionogi & Co., Ltd., and was acquired by Anthera Pharmaceuticals in 2006.{{cite press release|url=http://investor.anthera.com/releasedetail.cfm?ReleaseID=424037|date=6 September 2006|title=Anthera Licenses Portfolio of Anti-Inflammatory Products From Eli Lilly and Company and Shionogi & Co., Ltd.|publisher=Anthera Pharmaceuticals, Inc.}}

A Phase II study demonstrated selective sPLA2 inhibition as well as statistically significant anti-inflammatory responses and reductions in LDL cholesterol levels.{{cite press release|url=http://investor.anthera.com/releasedetail.cfm?ReleaseID=423153|date=6 May 2009|title=Anthera's Varespladib Meets Primary Endpoint In Phase 2 Francis Trial For The Treatment Of Acute Coronary Syndrome|publisher=Anthera Pharmaceuticals, Inc.}} 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.{{cite journal | vauthors = Rosenson RS, Elliott M, Stasiv Y, Hislop C | title = Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease | journal = European Heart Journal | volume = 32 | issue = 8 | pages = 999–1005 | date = April 2011 | pmid = 21081550 | doi = 10.1093/eurheartj/ehq374 | doi-access = free }}{{cite journal | vauthors = Rosenson RS, Hislop C, McConnell D, Elliott M, Stasiv Y, Wang N, Waters DD | title = 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 | journal = Lancet | volume = 373 | issue = 9664 | pages = 649–658 | date = February 2009 | pmid = 19231633 | doi = 10.1016/S0140-6736(09)60403-7 | s2cid = 30524226 }}{{cite journal | vauthors = Rosenson RS, Fraser H, Trias J, Hislop C | title = Varespladib methyl in cardiovascular disease | journal = Expert Opinion on Investigational Drugs | volume = 19 | issue = 10 | pages = 1245–1255 | date = October 2010 | pmid = 20809869 | doi = 10.1517/13543784.2010.517193 | s2cid = 207475608 }} Varespladib methyl has also been shown to further reduce LDL and inflammatory biomarker levels when administered in conjunction with a cholesterol lowering statin therapy.{{cite journal | vauthors = Rosenson RS, Hislop C, Elliott M, Stasiv Y, Goulder M, Waters D | title = Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients | journal = Journal of the American College of Cardiology | volume = 56 | issue = 14 | pages = 1079–1088 | date = September 2010 | pmid = 20863951 | doi = 10.1016/j.jacc.2010.06.015 | doi-access = free }}

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.{{cite press release|url=http://investor.anthera.com/releasedetail.cfm?ReleaseID=482003|date=23 June 2010|title=Anthera Enrolls First Patients in Pivotal Varespladib Phase 3 Clinical Study|publisher=Anthera Pharmaceuticals, Inc.}} The trial was halted in March 2012 due to insufficient efficacy.{{ClinicalTrialsGov|NCT01130246|VISTA-16 Trial: Evaluation of Safety and Efficacy of Short-term A-002 Treatment in Subjects With Acute Coronary Syndrome.}} 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.

First report on its efficacy as an antidote for snake venoms comes from 2016. 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.{{cite journal | vauthors = Williams DJ, Faiz MA, Abela-Ridder B, Ainsworth S, Bulfone TC, Nickerson AD, Habib AG, Junghanss T, Fan HW, Turner M, Harrison RA, Warrell DA | display-authors = 6 | title = Strategy for a globally coordinated response to a priority neglected tropical disease: Snakebite envenoming | journal = PLOS Neglected Tropical Diseases | volume = 13 | issue = 2 | pages = e0007059 | date = February 2019 | pmid = 30789906 | pmc = 6383867 | doi = 10.1371/journal.pntd.0007059 | doi-access = free }}

{{infobox drug

| drug_name = Varespladib methyl

| image = Varespladib methyl.svg

| pregnancy_AU =

| pregnancy_category = -

| legal_status = Investigational

| routes_of_administration = Oral

| bioavailability =

| metabolism =

| elimination_half-life =

| excretion =

| CAS_number = 172733-08-3

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_supplemental =

| ATC_prefix = none

| ATC_suffix =

| ATC_supplemental =

| PubChem = 9886917

| DrugBank =

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChemSpiderID = 8062590

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| UNII = 0NB98NBX3D

| UNII_Ref = {{fdacite|correct|FDA}}

| synonyms = A-002

| C = 22

| H = 22

| N = 2

| O = 5

| smiles = CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1

| StdInChI = 1S/C22H22N2O5/c1-3-15-20(21(26)22(23)27)19-16(24(15)12-14-8-5-4-6-9-14)10-7-11-17(19)29-13-18(25)28-2/h4-11H,3,12-13H2,1-2H3,(H2,23,27)

| StdInChIKey = VJYDOJXJUCJUHL-UHFFFAOYSA-N

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| verifiedrevid =

| Verifiedfields = changed

| pregnancy_US =

}}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).{{cite web|title=A-002: Short Term (16 week) Treatment of Acute Coronary Syndrome|url=http://www.anthera.com/products_a002.asp/|access-date=2011-08-17|publisher=Anthera Pharmaceuticals, Inc.}} Varespladib methyl is an orally bioavailable prodrug of the molecule varespladib.{{cite journal | vauthors = Fraser H, Hislop C, Christie RM, Rick HL, Reidy CA, Chouinard ML, Eacho PI, Gould KE, Trias J | display-authors = 6 | title = Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE-/- mice | journal = Journal of Cardiovascular Pharmacology | volume = 53 | issue = 1 | pages = 60–65 | date = January 2009 | pmid = 19129734 | doi = 10.1097/FJC.0b013e318195bfbc | s2cid = 36788997 }} 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.{{cite press release|publisher=Anthera Pharmaceuticals, Inc.|title=Anthera Licenses Portfolio of Anti-Inflammatory Products From Eli Lilly and Company and Shionogi & Co., Ltd.|date=6 September 2006|url=http://investor.anthera.com/releasedetail.cfm?ReleaseID=424037}}{{cite web|title=Science: sPLA2|url=http://www.anthera.com/science_spla2.asp|access-date=6 August 2011|publisher=Anthera Pharmaceuticals}} In March 2012, Anthera halted further investigation of varespladib per a recommendation from an independent Data Safety Monitoring Board. Varespladib and varespladib methyl were characterised as effective molecules in neutralization of snakes venoms{{cite journal | vauthors = Xiao H, Pan H, Liao K, Yang M, Huang C | title = Snake Venom PLA₂, a Promising Target for Broad-Spectrum Antivenom Drug Development | journal = BioMed Research International | volume = 2017 | pages = 6592820 | date = 2017 | pmid = 29318152 | pmc = 5727668 | doi = 10.1155/2017/6592820 | doi-access = free }} and are under experimental evaluation.{{cite journal | vauthors = Gutiérrez JM, Lewin MR, Williams DJ, Lomonte B | title = Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms | journal = Toxins | volume = 12 | issue = 2 | pages = 131 | date = February 2020 | pmid = 32093386 | pmc = 7076770 | doi = 10.3390/toxins12020131 | doi-access = free }}

{{infobox drug

| drug_name = Varespladib sodium

| verifiedrevid =

| image = Varespladib sodium.svg

| synonyms = A-001

| CAS_number = 172733-42-5

| CAS_supplemental =

| ATC_prefix = none

| ATC_suffix =

| ATC_supplemental =

| PubChem = 23674730

| DrugBank =

| ChemSpiderID = 137249

| ChEMBL = 2107809

| UNII = F6M52CDT0W

| KEGG = D06283

| C = 21

| H = 19

| N = 2

| Na = 1

| O = 5

| bioavailability =

| metabolism =

| elimination_half-life =

| excretion =

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category = —

| legal_status = Investigational

| routes_of_administration = IV

| smiles = CCC1=C(C2=C(N1CC3=CC=CC=C3)C=CC=C2OCC(=O)[O-])C(=O)C(=O)N.[Na+]

| StdInChI = 1S/C21H20N2O5.Na/c1-2-14-19(20(26)21(22)27)18-15(9-6-10-16(18)28-12-17(24)25)23(14)11-13-7-4-3-5-8-13;/h3-10H,2,11-12H2,1H3,(H2,22,27)(H,24,25);/q;+1/p-1

| StdInChIKey = XZZUHXILQXLTGV-UHFFFAOYSA-M

}}Varespladib sodium (also known as A-001, previously LY315920 and S-5920) is a sodium salt of varespladib designed for intravenous delivery.{{cite web|title=A-001: Prevention of Acute Chest Syndrome in Sickle Cell Disease.|publisher=Anthera Pharmaceuticals.|access-date=18 August 2011|url=http://www.anthera.com/products_a001.asp

}} 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.

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.{{cite journal | vauthors = Styles LA, Schalkwijk CG, Aarsman AJ, Vichinsky EP, Lubin BH, Kuypers FA | title = Phospholipase A2 levels in acute chest syndrome of sickle cell disease | journal = Blood | volume = 87 | issue = 6 | pages = 2573–2578 | date = March 1996 | pmid = 8630425 | doi = 10.1182/blood.V87.6.2573.bloodjournal8762573 | doi-access = free }}{{cite journal | vauthors = Styles LA, Aarsman AJ, Vichinsky EP, Kuypers FA | title = Secretory phospholipase A(2) predicts impending acute chest syndrome in sickle cell disease | journal = Blood | volume = 96 | issue = 9 | pages = 3276–3278 | date = November 2000 | pmid = 11050014 | doi = 10.1182/blood.V96.9.3276 }} 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.{{cite journal | vauthors = Bostrom MA, Boyanovsky BB, Jordan CT, Wadsworth MP, Taatjes DJ, de Beer FC, Webb NR | title = Group v secretory phospholipase A2 promotes atherosclerosis: evidence from genetically altered mice | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 27 | issue = 3 | pages = 600–606 | date = March 2007 | pmid = 17204667 | doi = 10.1161/01.ATV.0000257133.60884.44 | doi-access = free }}

Anthera Pharmaceuticals acquired varespladib sodium from Lilly and Shionogi in 2006. 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.{{cite press release|publisher=Anthera Pharmaceuticals, Inc.|title=Anthera's A-001 Receives Orphan Drug Status For The Prevention Of Acute Chest Syndrome In Patients With Sickle Cell Disease.|date=18 December 2007|url=http://investor.anthera.com/releasedetail.cfm?ReleaseID=423944

}} In 2009, Anthera Pharmaceuticals completed a Phase II study of varespladib sodium in subjects with sickle cell disease at risk for ACS.{{cite web|author=ClinicalTrials.gov.|title=IMPACTS Trial: Investigation of the Modulation of Phospholipase in Acute Chest Syndrome.|publisher=United States National Institute of Health.|access-date=18 August 2011|url=http://clinicaltrials.gov/ct2/show/NCT00434473

}}

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. 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. 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.

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. 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. 

In 2019, the U.S. Food and Drug Administration (FDA) designated varespladib orphan drug status for its potential to treat snakebite, without being FDA approved for Orphan Indication.{{Cite web|title=Search Orphan Drug Designations and Approvals|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm|website=www.accessdata.fda.gov|access-date=2020-05-27}}

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.{{cite journal | vauthors = Karakas M, Koenig W | title = Varespladib methyl, an oral phospholipase A2 inhibitor for the potential treatment of coronary artery disease | journal = IDrugs | volume = 12 | issue = 9 | pages = 585–592 | date = September 2009 | pmid = 19697278 }}

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.{{cite journal | vauthors = Mallat Z, Steg PG, Benessiano J, Tanguy ML, Fox KA, Collet JP, Dabbous OH, Henry P, Carruthers KF, Dauphin A, Arguelles CS, Masliah J, Hugel B, Montalescot G, Freyssinet JM, Asselain B, Tedgui A | display-authors = 6 | title = Circulating secretory phospholipase A2 activity predicts recurrent events in patients with severe acute coronary syndromes | journal = Journal of the American College of Cardiology | volume = 46 | issue = 7 | pages = 1249–1257 | date = October 2005 | pmid = 16198839 | doi = 10.1016/j.jacc.2005.06.056 | doi-access = free }}{{cite journal | vauthors = Kugiyama K, Ota Y, Takazoe K, Moriyama Y, Kawano H, Miyao Y, Sakamoto T, Soejima H, Ogawa H, Doi H, Sugiyama S, Yasue H | display-authors = 6 | title = Circulating levels of secretory type II phospholipase A(2) predict coronary events in patients with coronary artery disease | journal = Circulation | volume = 100 | issue = 12 | pages = 1280–1284 | date = September 1999 | pmid = 10491371 | doi = 10.1161/01.CIR.100.12.1280 | doi-access = free }}

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.{{cite journal | vauthors = Mallat Z, Lambeau G, Tedgui A | title = Lipoprotein-associated and secreted phospholipases A₂ in cardiovascular disease: roles as biological effectors and biomarkers | journal = Circulation | volume = 122 | issue = 21 | pages = 2183–2200 | date = November 2010 | pmid = 21098459 | doi = 10.1161/CIRCULATIONAHA.110.936393 | doi-access = free }}

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.

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.

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. They protected rodents against neurotoxicity and hemostatic toxicity, increasing survival of envenomed animals.

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{{Cite web | work = RCSB Protein Data Bank|title=RCSB PDB - 6PWH: Cystal structure of Myotoxin II from Bothrops moojeni co-crystallized with Varespladib (LY315920)|url=https://www.rcsb.org/structure/6PWH|access-date=2020-05-14 |language=en-US}}) 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.{{cite journal | vauthors = Salvador GH, Gomes AA, Bryan-Quirós W, Fernández J, Lewin MR, Gutiérrez JM, Lomonte B, Fontes MR | display-authors = 6 | title = Structural basis for phospholipase A₂-like toxin inhibition by the synthetic compound Varespladib (LY315920) | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 17203 | date = November 2019 | pmid = 31748642 | pmc = 6868273 | doi = 10.1038/s41598-019-53755-5 | bibcode = 2019NatSR...917203S | doi-access = free }}

{{reflist}}

• [http://www.anthera.com/products_a002.asp Varespladib methyl at Anthera.com]
• [http://www.anthera.com/products_a001.asp Varespladib sodium at Anthera.com]
• [http://clinicaltrials.gov/ct2/show/NCT01130246 Varespladib methyl Phase III study at ClinicalTrials.gov]
• [http://clinicaltrials.gov/ct2/show/NCT00434473 Varespladib sodium Phase II study at ClinicalTrials.gov]

{{Anti-inflammatory and antirheumatic products}}

{{Tryptamines}}

Category:1-Alkyltryptamines

Category:2-Alkyltryptamines

Category:Carboxamides

Category:Carboxylic acids

Category:4-Hydroxytryptamines

Category:Beta-Ketotryptamines