Darapladib (SB-480848) is a potent, selective, freely reversible, non-covalently bound, orally active inhibitor of Lp-PLA2 with an IC50 of 0.25 nM, and it serves as a predictive biomarker of inflammation in cardiovascular diseases like atherosclerosis.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is able to generate inflammatory products (lysophosphatidylcholine (lyso-PtdCho) and oxidised fatty acids).  And, it plays an important role in the development of high-risk lesions, in both the coronary and carotid arteries.

Darapladib is a selective inhibitor that targets the active-site serine residue of the enzyme Lp-PLA2.

Darapladib shows inhibition in plasma with an IC50 of 0.25 nM against recombinant human Lp-PLA2 (rhLp-PLA2). Moreover, it has good permeability of 0.10 cm/h (permeability >0.01 cm/h considered acceptable). This compound is freely reversible and non-covalently binds to rhLp-PLA2, with a Ki of 110 pM and off-rate of 27 min. And, it also shows potent inhibition in whole human plasma with an IC50 of 5 nM. Furthermore, the presence of darapladib prevents the production of lyso-PtdCho (IC50=43 nM) and subsequent monocyte chemotaxis (IC50=41 nM). Darapladib is also a potential anti-glioma compound. For instance, in rat glioma cells, darapladib inhibits cell growth, induces cell apoptosis, results in mitochondrial dysfunction, and reduces phosphorylation of AKT.

Besides the in vitro effects, darapladib also shows good in vivo profiles. For example, when orally administered 10 mg/kg in the WHHL rabbit, Darapladib shows effective prolonged inhibition of plasma Lp-PLA2 over 24 h (over 60% inhibition). What’s more, in male homozygous LDLR-deficient mice (C57/Bl6 genetic background), when the group receives Darapladib by gavage (50 mg/kg/d) once daily for 6 weeks, the inhibition of lp-PLA2 attenuates the inflammatory burden in serum, decreases the formation of atherosclerotic lesions and attenuates some inflammatory gene (MCP-1 and VCAM-1) expression at plaque lesions.

In conclusion, Darapladib has good in vitro and in vivo profiles as a Lp-PLA2 inhibitor. And, it can be used for atherosclerosis and glioma research.



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