Table 3. Physicochemical/ADME Properties for 16/17.
| properties | 16 | 17 |
|---|---|---|
| MW/eLogD/TPSAa | 296/3.3/78 | 297/2.8/91 |
| HLM Clu (mL/min/kg)b | 89 | 13 |
| solubility, pH 1.2, mg/mL | 13.0 | 3.96 |
| solubility, pH 6.5, mg/mL | 5.8 | 0.002 |
| MDR BA/AB ratioc | 2.7 | 1.1 |
| drug–drug interactions (DDI) | >30 μMd | >30 μMe |
| CYP inhibition IC50 | 3 μM (1A2) | |
| TDI,f % inhibition (dose) | 54% (30 μM) | 8% (30 μM) |
| 61% (60 μM) | 24% (60 μM) | |
| hERG IC50g | 1.8 μM | >10 μM |
| THLE IC50h | >119 μM | >300 μM |
| AMESi | Positive | Negative |
a
eLogD = measured logD at pH 7.4.
b
Free clearance calculated using measured protein binding in human liver microsomes (HLM).
c
MDR BA/AB efflux ratio using MDCK cell line transfected with human MDR1.
d
<15% Inhibition at 3 μM for isoforms (3A4, 2D6, 2C8, and 2C9).
e
<15% Inhibition at 3 μM for isoforms (3A4, 2D6, 1A2, 2C8, and 2C9).
f
Change in midazolam metabolism after incubation with compound.16
g
Measurement of potassium current in human embryonic kidney 293 (HEK293) cells stably transfected with the human ether-a-go-go-related gene (hERG) channel.
h
Transformed human liver epithelial cell assay (THLE).17
i
Activity in a bacterial mutagenesis assay.18