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Purity: ≥98%
Darapladib (formerly also known as SB-480848; SB 480848; SB480848), a substituted pyrimidone, is a novel, potent and reversible inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor with potential anti-inflammatory activity. It inhibits Lp-PLA2 with an IC50 of 0.25 nM. Darapladib is under development in Phase 3 clinical trials for the treatment of atherosclerosis.
| ln Vitro |
In C6 glioma cells and U251MG, darapladib (5 μM; 6, 12 h) can cause cell cycle arrest [2]. Glioma cell apoptosis is triggered by darapladib (5 μM; 3, 6 h) [2]. In glioma cells, darapladib (5 μM; 5, 15, 30, 60, and 90 min) can cause an increase in ERK1/2 protein phosphorylation [2].
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| ln Vivo |
In mice lacking LDLR, darapladib (50 mg/kg; po; once daily for 6 weeks) can considerably reduce serum Lp-PLA2 activity [3]. In mice, darapladib (50 mg/kg; po; once daily for 6 weeks) can lower the levels of IL-6 and hs-CRP in the serum [3].
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| Cell Assay |
Apoptosis Analysis[2]
Cell Types: C6 glioma cells and U251MG cells. Tested Concentrations: 5 μM Incubation Duration: 3, 6 h Experimental Results: Triggered cell apoptosis in glioma cells. Cell Cycle Analysis[2] Cell Types: C6 glioma cells and U251MG cells. Tested Concentrations: 5 μM Incubation Duration: 6, 12 h Experimental Results: Induced cell cycle arrest in glioma cells. Western Blot Analysis[2] Cell Types: C6 glioma cells and U251MG cells. Tested Concentrations: 5 μM Incubation Duration: 5, 15, 30, 60 and 90 min Experimental Results: Induced an increase in phosphorylation of ERK1/2 proteins, but decreased AKT phosphorylation in glioma cells. |
| Animal Protocol |
Animal/Disease Models: Male homozygous LDLR-deficient mice (C57/Bl6 genetic background)[3].
Doses: 50 mg/kg Route of Administration: Oral administration; one time/day for 6 weeks. Experimental Results: Dramatically inhibited activity of serum Lp-PLA2. |
| References |
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| Additional Infomation |
Darapladib is a substituted pyrimidone with inhibitory activity towards lipoprotein-associated phospholipase-A2 (Lp-PLA2), an important regulator of lipid metabolism and inflammation that circulates with lipoprotein particles and is carried into the arterial wall with low-density lipoprotein particles during the progression of atherosclerosis.
Drug Indication Investigated for use/treatment in atherosclerosis. Mechanism of Action Darapladib is a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor. Lp-PLA2 is an enzymatic upstream mediator of inflammatory processes. Evidence from experimental settings show that the breakdown products from oxidized low density lipoprotein C (LDL-C)such as lysophosphatidylcholine species and oxidized nonesterified fatty acids are pro-inflammatory and pro-apoptotic. These products are suspected to cause athlerosclerosis progression and plaque vulnerability, which leads to increased risk of cardiovascular problems. |
| Molecular Formula |
C36H38F4N4O2S
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|---|---|
| Molecular Weight |
666.7711
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| Exact Mass |
666.265
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| CAS # |
356057-34-6
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| Related CAS # |
1389264-17-8 (Darapladib-impurity)
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| PubChem CID |
9939609
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
741.0±70.0 °C at 760 mmHg
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| Flash Point |
401.9±35.7 °C
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| Vapour Pressure |
0.0±2.4 mmHg at 25°C
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| Index of Refraction |
1.594
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| LogP |
8.27
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
47
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| Complexity |
1120
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
WDPFJWLDPVQCAJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C36H38F4N4O2S/c1-3-42(4-2)20-21-43(22-25-8-12-27(13-9-25)28-14-16-29(17-15-28)36(38,39)40)33(45)23-44-32-7-5-6-31(32)34(46)41-35(44)47-24-26-10-18-30(37)19-11-26/h8-19H,3-7,20-24H2,1-2H3
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| Chemical Name |
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]-1H-Cyclopentapyrimidine-1-acetamide
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| Synonyms |
SB-480848; SB 480848; Darapladib;SB480848
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.75 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.75 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.75 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4998 mL | 7.4988 mL | 14.9977 mL | |
| 5 mM | 0.3000 mL | 1.4998 mL | 2.9995 mL | |
| 10 mM | 0.1500 mL | 0.7499 mL | 1.4998 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01873339 | Completed | Drug: Darapladib Drug: Midazolam |
Atherosclerosis | GlaxoSmithKline | June 19, 2013 | Phase 1 |
| NCT02000804 | Completed | Drug: darapladib 160mg | Atherosclerosis | GlaxoSmithKline | October 23, 2013 | Phase 1 |
| NCT01852565 | Completed | Drug: Darapladib Drug: Diltiazem |
Atherosclerosis | GlaxoSmithKline | May 14, 2013 | Phase 1 |
| NCT00704431 | Completed | Drug: SB-480848 (darapladib) | Atherosclerosis | GlaxoSmithKline | May 2008 | Phase 1 |
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