Darbufelone (CI-1004) is a dual inhibitor of cellular PGF2α and LTB4 production, it is also a COX-2 inhibitor potentially for the treatment of rheumatoid arthritis. Darbufelone potently inhibits PGHS-2 (IC50=0.19 μM) but is much less potent with PGHS-1 (IC50=20 μM). The IC50 of A549 and H520 are 20±3.6 and 21±1.8 μM, respectively, while the H460 has much lower IC50 (15±2.7 μM).
Darbufelone is orally active and nonulcerogenic in animal models of inflammation and arthritis. The tumor volumes decrease in a time-dependent manner on mice treated with Darbufelone (80 mg/kg/day). In contrast, lower dose of Darbufelone (20 or 40 mg/kg/day) dos not show any significant inhibition of tumor weight. At necropsy, the tumor weight in mice treated with Darbufelone (80 mg/kg/day) is reduced by 30.2% in comparison with control group.
| Cell Experiment | |
|---|---|
| Cell lines | A549, NCI-H520 and NCI-H460 cells |
| Preparation method | In brief, tumor cells growing in log-phase are trypsinized and seeded at 5×103 cells per well into 96-well plates and allowed to attach overnight. Medium in each well is replaced with fresh medium or medium containing various concentrations of Darbufelone (5-60 μM) in at least triplicate wells. Cells are cultured to another 72 h. After treatment, 1/10 volume of MTT solution (5 mg/mL) is added to each well, and the plate is incubated at 37°C for another 4 h. Two hundred microliters of DMSO is added to each well to solubilize the MTT-formazan product after removal of the medium. Absorbance at 595 nm is measured with a multi-well spectrophotometer. Growth inhibition is calculated as a percentage of the untreated controls. |
| Concentrations | 5-60 μM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | C57Bl/6 male mice implanted Lewis Lung Carcinoma cells |
| Formulation | CMC-Na |
| Dosages | 20, 40, and 80 mg/kg/day |
| Administration | gavage |
| Molecular Weight | 332.46 |
| Formula | C18H24N2O2S |
| CAS Number | 139226-28-1 |
| Storage | -20°C, dry, sealed |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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