Darapladib

Darapladib is a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) with IC50 of 0.25 nM.

Signaling Pathways >> Metabolic Enzyme/Protease >> Phospholipase

Research Areas >> Cardiovascular Disease

IC50: 0.25 nM (Lp-PLA2)[1]

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 Ki 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].

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].

Mice[2] Male homozygous LDLR-deficient mice (C57/Bl6 genetic background) are fed a high-fat diet consisting of 18% hydrogenated cocoa butter, 0.15% cholesterol, 7% casein, 7% sucrose, and 3% maltodextrin for 17 weeks, beginning at 6 weeks of age. Forty mice are divided into two groups (n=20 per group) randomly. One group receive Darapladib by gavage (50 mg/kg per day) once daily, while the other group receive the vehicle (saline). During the 6 weeks of treatment, all mice are housed in a room with a 12-h light/dark cycle and are allowed free access to a high-fat diet and water.

[1]. Blackie JA, et al. The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett. 2003 Mar 24;13(6):1067-70.

[2]. Hu MM, et al. The inhibition of lipoprotein-associated phospholipase A2 exerts beneficial effects against atherosclerosis inLDLR-deficient mice. Acta Pharmacol Sin. 2011 Oct;32(10):1253-1258.

U73122 | D609 | Quinacrine (dihydrochloride) | FIPI | Melittin | Varespladib | CAY10650 | AA26-9 | ML348 | Tanshinone I | Methyl Arachidonyl Fluorophosphonate | ML 349 | 1-Monolinolein | Lp-PLA2 -IN-1 | SPK-601