Darapladib

SKU: orb1225215

Description

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).\n(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.

Key Properties

• CAS Number: 356057-34-6
• MW: 666.7711
• Purity: >98% (HPLC)
• Formula: C₃₆H₃₈F₄N₄O₂S
• SMILES: 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
• Target: Phospholipase
• Solubility: 10 mM in DMSO

Bioactivity

• In Vivo:
  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.
• In Vitro:
  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.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

SB-480848 | SB480848 | SB 480848

Quick Database Links

Gene Symbol

Phospholipase