Varespladib

Varespladib
Clinical data
Pregnancy
category
  • —
ATC code
  • none
Legal status
Legal status
  • investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H20N2O5
Molar mass380.400 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) ☒N
  • Key:BHLXTPHDSZUFHR-UHFFFAOYSA-N ☒N
 ☒NcheckY (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.

  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. 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.
  5. ^ "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. 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
  8. ^ a b Nicholls SJ, Kastelein JJ, Schwartz GG, Bash D, Rosenson RS, Cavender MA, et al. (January 2014). "Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial". JAMA. 311 (3): 252–262. doi:10.1001/jama.2013.282836. PMID 24247616.
  9. ^ Salvador GH, Gomes AA, Bryan-Quirós W, Fernández J, Lewin MR, Gutiérrez JM, et al. (November 2019). "Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920)". Scientific Reports. 9 (1): 17203. Bibcode:2019NatSR...917203S. doi:10.1038/s41598-019-53755-5. PMC 6868273. PMID 31748642.
  10. ^ Lewin MR, Gilliam LL, Gilliam J, Samuel SP, Bulfone TC, Bickler PE, Gutiérrez JM (November 2018). "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. doi:10.3390/toxins10110479. PMC 6265968. PMID 30453607.
  11. ^ Bryan-Quirós W, Fernández J, Gutiérrez JM, Lewin MR, Lomonte B (January 2019). "Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A2". Toxicon. 157: 1–7. doi:10.1016/j.toxicon.2018.11.292. PMID 30447275. S2CID 53669789.
  12. ^ Wang Y, Zhang J, Zhang D, Xiao H, Xiong S, Huang C (February 2018). "Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation". Molecules. 23 (2): 391. doi:10.3390/molecules23020391. PMC 6017252. PMID 29439513.
  13. ^ Lewin M, Samuel S, Merkel J, Bickler P (August 2016). "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. doi:10.3390/toxins8090248. PMC 5037474. PMID 27571102.