Varespladib

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Varespladib
Varespladib.svg
Clinical data
Pregnancy
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  • none
Legal status
Legal status
  • investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
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KEGG
ChEBI
ChEMBL
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Chemical and physical data
Formula C21H20N2O5
Molar mass 380.400 g·mol−1
3D model (JSmol)
  • CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1
  • InChI=1S/C21H20N2O5/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) X mark.svgN
  • Key:BHLXTPHDSZUFHR-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (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.

Contents

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
Pregnancy
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Routes of
administration 		Oral
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  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C22H22N2O5
Molar mass 394.427 g·mol−1
3D model (JSmol)
  • CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1
  • InChI=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) X mark.svgN
  • Key:VJYDOJXJUCJUHL-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)

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
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H19N2NaO5
Molar mass 402.382 g·mol−1
3D model (JSmol)
  • CCC1=C(C2=C(N1CC3=CC=CC=C3)C=CC=C2OCC(=O)[O-])C(=O)C(=O)N.[Na+]
  • InChI=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
  • Key: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. [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]

Related Research Articles

<span class="mw-page-title-main">Antivenom</span> Medical treatment for venomous bites and stings

Antivenom, also known as antivenin, venom antiserum, and antivenom immunoglobulin, is a specific treatment for envenomation. It is composed of antibodies and used to treat certain venomous bites and stings. Antivenoms are recommended only if there is significant toxicity or a high risk of toxicity. The specific antivenom needed depends on the species involved. It is given by injection.

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 (ASCVD), which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't 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. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

<span class="mw-page-title-main">Snakebite</span> Injury caused by bite from snakes

A snakebite is an injury caused by the bite of a snake, especially a venomous snake. A common sign of a bite from a venomous snake is the presence of two puncture wounds from the animal's fangs. Sometimes venom injection from the bite may occur. This may result in redness, swelling, and severe pain at the area, which may take up to an hour to appear. Vomiting, blurred vision, tingling of the limbs, and sweating may result. Most bites are on the hands, arms, or legs. Fear following a bite is common with symptoms of a racing heart and feeling faint. The venom may cause bleeding, kidney failure, a severe allergic reaction, tissue death around the bite, or breathing problems. Bites may result in the loss of a limb or other chronic problems or even death.

<span class="mw-page-title-main">Snake venom</span> Highly modified saliva containing zootoxins

Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is injected by unique fangs during a bite, whereas some species are also able to spit venom.

Phospholipase A<sub>2</sub> Peripheral membrane protein

The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule:

<span class="mw-page-title-main">Envenomation</span> Process of venom injection

Envenomation is the process by which venom is injected by the bite or sting of a venomous animal.

<span class="mw-page-title-main">Indian cobra</span> Species of snake

The Indian cobra, also known commonly as the spectacled cobra, Asian cobra, or binocellate cobra, is a species of cobra, a venomous snake in the family Elapidae. The species is native to the Indian subcontinent, and is a member of the "big four" species that are responsible for the most snakebite cases in India.

<span class="mw-page-title-main">Mamushi</span> Species of snake

Gloydius blomhoffii, commonly known as the mamushi, Japanese moccasin, Japanese pit viper, Qichun snake, Salmusa or Japanese mamushi, is a venomous pit viper species found in Japan. It was once considered to have 4 subspecies, but it is now considered monotypic.

Taipoxin is a potent myo- and neurotoxin that was isolated from the venom of the coastal taipan Oxyuranus scutellatus or also known as the common taipan. Taipoxin like many other pre-synaptic neurotoxins are phospholipase A2 (PLA2) toxins, which inhibit/complete block the release of the motor transmitter acetylcholine and lead to death by paralysis of the respiratory muscles (asphyxia). It is the most lethal neurotoxin isolated from any snake venom to date.

Venom-induced consumption coagulopathy (VICC) is a medical condition caused by the effects of some snake and caterpillar venoms on the blood. Important coagulation factors are activated by the specific serine proteases in the venom and as they become exhausted, coagulopathy develops. Symptoms are consistent with uncontrolled bleeding. Diagnosis is made using blood tests that assess clotting ability along with recent history of envenomation. Treatment generally involves pressure dressing, confirmatory blood testing, and antivenom administration.

<span class="mw-page-title-main">PLA2G1B</span> Protein-coding gene in the species Homo sapiens

Phospholipase A2, group 1B is an enzyme that in humans is encoded by the PLA2G1B gene.

<span class="mw-page-title-main">Ticagrelor</span> Coronary medication

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

Darapladib is an inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) that is in development as a drug for treatment of atherosclerosis.

<span class="mw-page-title-main">Lipoprotein-associated phospholipase A2</span> Protein-coding gene in the species Homo sapiens

Lipoprotein-associated phospholipase A2 (Lp-PLA2) also known as platelet-activating factor acetylhydrolase (PAF-AH) is a phospholipase A2 enzyme that in humans is encoded by the PLA2G7 gene. Lp-PLA2 is a 45-kDa protein of 441 amino acids. It is one of several PAF acetylhydrolases.

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

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<span class="mw-page-title-main">Samar cobra</span> Species of snake

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Crotoxin (CTX) is the main toxic compound in the snake venom of the South American rattlesnake, Crotalus durissus terrificus. Crotoxin is a heterodimeric beta-neurotoxin, composed of an acidic, non-toxic and non-enzymatic subunit (CA), and a basic, weakly toxic, phospholipase A2 protein (CB). This neurotoxin causes paralysis by both pre- and postsynaptic blocking of acetylcholine signalling.

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

Lysine acetylsalicylate, also known as aspirin DL-lysine or lysine aspirin, is a more soluble form of acetylsalicylic acid (aspirin). As with aspirin itself, it is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, antithrombotic and antipyretic properties. It is composed of the ammonium form of the amino acid lysine paired with the conjugate base of aspirin.

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References

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  2. ↑ "A-002: Short Term (16 week) Treatment of Acute Coronary Syndrome". Anthera Pharmaceuticals. Retrieved 6 September 2011.
  3. ↑ "Varespladib". American Journal of Cardiovascular Drugs. 11 (2): 137–143. April 2011. doi:10.2165/11533650-000000000-00000. PMID   21446779.
  4. ↑ Baynes JW, Dominiczak MH (2005). Medical Biochemistry (2 ed.). Elsevier Mosby. pp.  555. ISBN   0-7234-3341-0.
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  6. ↑ "Science: sPLA2". Anthera Pharmaceuticals. Retrieved 6 August 2011.
  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
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  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.
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  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
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  25. 1 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.
  26. ↑ "Science: sPLA2". Anthera Pharmaceuticals. Retrieved 6 August 2011.
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  28. 1 2 Gutiérrez JM, Lewin MR, Williams DJ, Lomonte B (February 2020). "Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms". Toxins. 12 (2): 131. doi: 10.3390/toxins12020131 . PMC   7076770 . PMID   32093386.
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  34. ↑ ClinicalTrials.gov. "IMPACTS Trial: Investigation of the Modulation of Phospholipase in Acute Chest Syndrome". United States National Institute of Health. Retrieved 18 August 2011.
  35. ↑ "Search Orphan Drug Designations and Approvals". www.accessdata.fda.gov. Retrieved 2020-05-27.
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