Darapladib

Research use only, not for human use.

A potent Lp-PLA2 inhibitor with IC50 of 0.25 nM.

A potent Lp-PLA2 inhibitor with IC50 of 0.25 nM; shows an enhanced in vitro and in vivo profile versus SB-435495.Atherosclerosis Phase 3 Discontinued(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 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). (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. 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.

Apoptosis Analysis Cell Line:C6 glioma cells and U251MG cells.Concentration:5 μM Incubation Time:3, 6 h Result:Triggered cell apoptosis in glioma cells. Cell Cycle Analysis Cell Line:C6 glioma cells and U251MG cells.Concentration:5 μM Incubation Time:6, 12 h Result:Induced cell cycle arrest in glioma cells.Western Blot Analysis Cell Line:C6 glioma cells and U251MG cells.Concentration:5 μM Incubation Time:5, 15, 30, 60 and 90 min Result:Induced an increase in phosphorylation of ERK1/2 proteins, but reduced AKT phosphorylation in glioma cells.

Animal Model:Male homozygous LDLR-deficient mice (C57/Bl6 genetic background).Dosage:50 mg/kg Administration:Oral administration; once daily for 6 weeks.Result:Significantly inhibited activity of serum Lp-PLA2.

SB-480848 | SB480848 | SB 480848

Metabolic Enzyme/Protease

Phospholipase

Lp-PLA2

Cardiovascular Disease

Atherosclerosis

356057-34-6

666.7711

C36H38F4N4O2S

>98% (HPLC)

10 mM in DMSO

O=C(N(CCN(CC)CC)CC1=CC=C(C2=CC=C(C(F)(F)F)C=C2)C=C1)CN(C3=C4CCC3)C(SCC5=CC=C(F)C=C5)=NC4=O

1H-Cyclopentapyrimidine-1-acetamide, N-[2-(diethylamino)ethyl]-2-[[(4-fluorophenyl)methyl]thio]-4,5,6,7-tetrahydro-4-oxo-N-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-

(-20℃)

With Ice Pack

≥ 2 years