Darapladib

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

Darapladib

Clinical data
Other names	SB-480848
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	Investigational
Identifiers
IUPAC name 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	356057-34-6^Y
PubChem CID	9939609
IUPHAR/BPS	6696
ChemSpider	8115230^N
UNII	UI1U1MYH09
KEGG	D03650^N
ChEMBL	ChEMBL204021^N
PDB ligand	5HV (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID70189073
ECHA InfoCard	100.130.738
Chemical and physical data
Formula	C36H38F4N4O2S
Molar mass	666.78 g·mol^−1
3D model (JSmol)	Interactive image
SMILES 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 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^N Key:WDPFJWLDPVQCAJ-UHFFFAOYSA-N^N
^NY (what is this?)  (verify)

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.

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. . 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.