Table 2. ADME of Fluorinated Analogues 9, 10, 12, and 13.
| compound | 9 | 10 | 12 | 13 | ||
|---|---|---|---|---|---|---|
| cLogPa | 3.39 | 3.71 | 3.19 | 3.41 | ||
| LiPEb | 3.1 | 4.0 | 4.2 | 4.1 | ||
| in vitro ADME | Clint (μL/min/mg protein)c | mouse | 61.3 | 193 | 131 | 159 |
| rat | 25.7 | 86.1 | 71.3 | 99.6 | ||
| dog | 35.3 | 68.9 | 52.4 | 73.9 | ||
| human | 35.4 | 83.8 | 73.6 | 104 | ||
| PPB (% bound)d | mouse | 99.7 | 99.4 | 97.8 | 97.9 | |
| rat | 97.4 | 92.4 | 83.1 | 89.9 | ||
| dog | 96.3 | 93.6 | 64.3 | 90.3 | ||
| human | 95.9 | 94.7 | 83.3 | 92.8 | ||
| CYP inh. (% at 10 μM)e | 3A4 | 5.0 | 0 | 25.2 | 0 | |
| 2D6 | 17.2 | 7.7 | 26.1 | 9.5 | ||
| 2C8 | 23.1 | 50.9 | 18.9 | 41 | ||
| 1A2 | 19.4 | 0 | 28.6 | 15 | ||
| 2C9 | 11.6 | 5.0 | 25.4 | 11.1 | ||
a
ClogP values were generated with ChemDraw Professional 15.0.
b
LiPE = lipophilic efficiency = pEC50 – cLogP (ChemDraw 15.0).
c
Intrinsic clearance (Clint) of compounds in mouse/rat/dog/human liver microsomes (expressed in μL/min/mg protein).
d
Measured in vitro binding of compounds to mouse/rat/dog/human plasma protein bindings (expressed in % bound).
e
In vitro inhibition of cytochrome P450 isoforms at single concentration (10 μM).