Darapladib is a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA₂) with IC₅₀ of 0.25 nM. IC50 & Target: IC50: 0.25 nM (Lp-PLA₂)^[1] In Vitro: Mechanistic studies using steady state and transient kinetics indicate Darapladib (SB-480848) to be a freely reversible, non-covalently bound, inhibitor of rhLp-PLA₂ with a K_i of 110 pM and an off-rate of 27 min. Potent inhibition of the enzyme in whole human plasma is confirmed (IC₅₀=5±2 nM). Furthermore, the presence of Darapladib during the copper catalysed oxidation of human LDL prevents the production of lyso-PtdCho (IC₅₀=4±3 nM) and subsequent monocyte chemotaxis (IC₅₀=4±1 nM)^[1]. In Vivo: Additional in vivo studies with Darapladib indicated an oral bioavailability of 11±2% in the fed rat. The oral bioavailability of Darapladib is 28±4% in the dog. Furthermore excellent inhibition of Lp-PLA₂ within the atherosclerotic plaque is achieved for Darapladib, with 95±1% inhibition observed 2 h after an oral dose of 30 mg/kg to the WHHL rabbit^[1]. Darapladib, a specific inhibitor of lipoprotein-associated phospholipase A2 (lp-PLA₂), on inflammation and atherosclerotic formation in the low density lipoprotein receptor (LDLR)-deficient mice. the activity of serum lp-PLA₂ is inhibited by more than 60% in LDLR-deficient mice after oral administration of 50 mg/kg once daily of Darapladib for 6 weeks. Darapladib significantly inhibits serum lp-PLA₂ activity in LDLR-deficient mice^[2].