Table 2. Safety and Pharmacokinetic Profile of Compounds 3 and 8In Vitro.
| 3 | 8 | |
|---|---|---|
| CYP inhibition (IC50, μM)a | ||
| 1A2 | >100.0 | 45.5 |
| 2C9 | 25.0 | 25.2 |
| 2C19 | 18.3 | 19.0 |
| 2D6 | 29.3 | 26.7 |
| 3A4 | 41.0 | 20.8 |
| cardiotoxicity (IC50, μM) | ||
| hERG ligand binding assay | 50.0 | >10 |
| liver microsomal phase-I stabilityb | ||
| rat (%) | 67.9 ± 0.4 | 54.1 ± 2.3 |
| human (%) | 68.1 ± 2.5 | 40.5 ± 3.2 |
| rat (t1/2, min) | 52.0 ± 2.2 | 29.3 ± 0.7 |
| human (t1/2, min) | 74.4 ± 4.5 | 30.6 ± 0.8 |
| plasma stabilityc | ||
| rat (%) | 84.6 ± 2.6 | 99.6 ± 6.0 |
| human (%) | 93.6 ± 4.2 | 100.0 ± 11.1 |
| plasma protein bindingd | ||
| rat (%) | 92.7 ± 2.6 | 89.2 ± 2.7 |
| human (%) | 96.5 ± 1.2 | 97.1 ± 0.6 |
a
IC50 (μM) in human liver microsomes determined using cocktail substrate assays.
b
Liver microsomal phase-I stability (% remaining after 30 min).
c
Ratio (%) remaining after 4 h of incubation at 37 °C.
d
Plasma protein binding rate (%). Assay conditions are described in the Supporting Information. All data are shown as the mean ± SD; n = 3 for all.