In vitro: BMS-309403 binds to FABP4 with high affinity and shows over 100-fold selectivity against FABP5 as well as the heart isoform FABP3. BMS-309403 interacts with the fatty-acid-binding pocket within the interior of the protein and competitively inhibits the binding of endogenous fatty acids. Treatment with BMS-309403 significantly decreased MCP-1 production from THP-1 macrophages in a dose- and time-dependent manner. BMS-309403 stimulates glucose uptake in C2C12 myotubes in a temporal and dose dependent manner via activation of AMP-activated protein kinase (AMPK) signaling pathway but independent of FABPs.
In vivo: A 6 week treatment with BMS-309403 improves endothelial function, phosphorylated and total eNOS and reduced plasma triglyceride levels but does not affect endothelium-independent relaxations. In cultured human microvascular endothelial cells, lipid-induced A-FABP expression is associated with reduced phosphorylated eNOS and NO production and is reversed by BMS-309403. The extent of atherosclerotic lesion area in the proximal aorta is significantly reduced in the BMS-309403-treated group compared with vehicle-treated controls in both the early and late intervention studies.
| Cell Experiment | |
|---|---|
| Cell lines | IL-4-stimulated cells |
| Preparation method | LPL expression correlated with increased very low density lipoprotein (VLDL)- induced triglyceride accumulation in IL-4-polarized macrophages, which was sensitive to inhibition of lipolysis or PPARg antagonism. Inhibition of FABP4 during differentiation using chemical inhibitors BMS309403 and HTS01037 or FABP4 siRNA decreased the expression of FABP4 and LPL, and reduced lipid accumulation in macrophages treated with VLDL. |
| Concentrations | 50 mM |
| Incubation time | 6 h |
| Animal Experiment | |
|---|---|
| Animal models | C57BL/6J male mice |
| Formulation | PBS |
| Dosages | 15 mg/kg/day |
| Administration | i.v. |
| Molecular Weight | 474.55 |
| Formula | C31H26N2O3 |
| CAS Number | 300657-03-8 |
| Solubility (25°C) | 62.5 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| 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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