Darapladib

Last updated

Darapladib
Darapladib structure.svg
Clinical data
Other namesSB-480848
Routes of
administration
By mouth
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
  • N-(2-Diethylaminoethyl)-2-[2-[(4-fluorophenyl)methylsulfanyl]-4-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-1-yl]-N-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]acetamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.130.738 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C36H38F4N4O2S
Molar mass 666.78 g·mol−1
3D model (JSmol)
  • FC(F)(F)c1ccc(cc1)c2ccc(cc2)CN(C(=O)CN\4C(\SCc3ccc(F)cc3)=N/C(=O)/C5=C/4CCC5)CCN(CC)CC
  • InChI=1S/C36H38F4N4O2S/c1-3-42(4-2)20-21-43(22-25-8-12-27(13-9-25)28-14-16-29(17-15-28)36(38,39)40)33(45)23-44-32-7-5-6-31(32)34(46)41-35(44)47-24-26-10-18-30(37)19-11-26/h8-19H,3-7,20-24H2,1-2H3 X mark.svgN
  • Key:WDPFJWLDPVQCAJ-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Darapladib is an inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) that is in development as a drug for treatment of atherosclerosis. [1]

It was discovered by Human Genome Sciences in collaboration with GlaxoSmithKline (GSK). [2]

In November 2013, GSK announced that the drug had failed to meet Phase III endpoints in a trial of 16,000 patients with acute coronary syndrome (ACS). [3] An additional trial of 13,000 patients (SOLID-TIMI 52) finished in May 2014. The study failed to reduce the risk of coronary heart disease death, myocardial infarction, and urgent coronary revascularization compared with placebo in acute coronary syndrome patients treated with standard medical care. [4]

In 2022, Darapladib has been found to inhibit intraerythrocytic development of the malaria parasite Plasmodium falciparum by inhibition of the human host enzyme peroxiredoxin 6. [5] The authors present data that the original target of Darapladib, Lp-PLA2, is absent in the host red blood cell.

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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.

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References

  1. Thompson PL, Nidorf SM, Eikelboom J (August 2013). "Targeting the unstable plaque in acute coronary syndromes". Clinical Therapeutics. 35 (8): 1099–107. doi:10.1016/j.clinthera.2013.07.332. PMID   23973042.
  2. "Spotlight on Glaxo Heart Drug as Others Fail". CNBC . Reuters. 12 April 2007.
  3. Carroll J (12 November 2013). "GlaxoSmithKline loses its first big PhIII bet on heart drug darapladib". Fierce Biotech.
  4. "GSK announces phase III study with darapladib did not meet primary endpoint in patients following an acute coronary syndrome". GlaxoSmithKline plc. 13 May 2014. Archived from the original on 14 July 2014. Retrieved 2 July 2014.
  5. Wagner MP, Formaglio P, Gorgette O, Dziekan JM, Huon C, Berneburg I, Rahlfs S, Barale JC, Feinstein SI, Fisher AB, Ménard D, Bozdech Z, Amino R, Touqui L, Chitnis CE (June 2022). "Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target". Cell Rep. 39 (11): 110923. doi:10.1016/j.celrep.2022.110923. hdl: 10356/164886 . PMID   35705035.