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 K_i 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.

Reference

[1] Blackie JA, et al. Bioorg Med Chem Lett. 2003 Mar 24;13(6):1067-70.

[2] Bui QT, et al. Expert Opin Investig Drugs. 2010 Jan;19(1):161-8.

[3] Hu MM, et al. Acta Pharmacol Sin. 2011 Oct;32(10):1253-8.

[4] Wang YJ, et al. Toxicol Appl Pharmacol. 2020 Sep 1;402:115133.