Table 5.
In Vitro ADMET Profile of 55, 39, and BMS-626529
| Compound | ||||
|---|---|---|---|---|
| Assay performed | in vitro ADMET | 39 | 55 | BMS-626529 |
| Solubility Range when prepared at 500 μM | With 5% DMSO, pH7.4 | ~500 | 100–500 | 100–500 |
| (~206 μg/mL) | (42.4–214 μg/mL) | (47.3–237 μg/mL) | ||
| With 5% DMSO, pH7.4 | 100–500 | 100–500 | <100 | |
| (41.3–206 μg/mL) | (42.8–214 μg/mL) | (<47.3 μg/mL) | ||
| Caco-2 permeability (mean Papp, × 10−6 cm/sec) | A-B (pH 7.4/7.4) | 0.471 | 0.602 | 9.27 |
| B-A (pH 7.4/7.4) | 17.0 | 17.7 | 32.0 | |
| Efflux Ratio | 36.4 | 30.5 | 3.46 | |
| A-B (pH 7.4/7.4) with 100 μM verapamil | 0.837 | 0.777 | 13.5 | |
| B-A (pH 7.4/7.4) with 100 μM verapamil | 11.0 | 10.9 | 22.7 | |
| Efflux Ratio with 100 μM verapamil | 13.3 | 14.4 | 1.69 | |
| Metabolic Stability (human liver microsomes) | parent compound remaining at 120 min (% of 0 min) | 90.4 | 88.5 | 71.5 |
| Clint (μl/min/mg protein) | 1.6 | 1.8 | 5.19 | |
| Protein binding (human plasma) | mean fraction unbound, % | 0.281 | 0.949 | 13.1 |
| Cytochrome P450 inhibition, IC50 (μM) | CYP1A2 (Phenacetin) | > 25 | > 25 | > 25 |
| CYP2B6 (Bupropion) | > 25 | > 25 | > 25 | |
| CYP2C8 (Paclitaxel) | > 25 | > 25 | > 25 | |
| CYP2C9 (Diclofenac) | > 25 | > 25 | > 25 | |
| CYP2C19 (Mephenytoin) | > 25 | > 25 | > 25 | |
| CYP2D6 (Bufuralol) | > 25 | > 25 | > 25 | |
| CYP3A4 (Testosterone) | > 25 | > 25 | > 25 | |
| CYP3A4 (Midazolam) | > 25 | > 25 | > 25 | |
| hERG channel inhibition, IC50 (μM) | 0.9 | 3.0 | 21.9 | |