Table 4.
Properties of 27 (HCl Salt) in Vitro
| solubility (PBS, pH 7.4, μM)a | hERG Inhibition, IC50 (μM)b | CYP inhibition (% at 10 μM)c | metabolic stability in human hepatocytesd | protein binding (%)e |
|---|---|---|---|---|
| 73.43 | 29.258 | 1A2 (2.29) | in vitro T1/2 (min): 202.00 | 97.98 |
| 2A6 (7.47) | ||||
| 2C8 (84.23) | ||||
| 2C9 (30.74) | in vitro Clint ((μL/min)/106 cells): 6.86 | |||
| 2C19 (31.79) | ||||
| 2D6 (14.50) | ||||
| 3A4 (50.61) |
a
Kinetic solubility. For reference, the solubility of progesterone is 22.37 μM.
b
HEK293 cell line stably transfected with hERG gene is employed, and dofetilide is used as a positive control (IC50 = 0.015 μM).
c
For reference, the inhibitory percentages of subtypes of CYP by known inhibitors at 10 μM are CYP1A2 (phenacetin, 83.68), CYP2A6 (coumarin, 98.19), CYP2C8 (paclitaxel, 80.89), CYP2C9 (tolbutamide, 87.68), CYP2C19 (mephenytoin, 96.83), CYP2D6 (dextromethorphan, 94.37), and CYP3A4 (midazolam, 99.46).
d
For reference, in vitro T1/2 and in vitro Clint of verapamil is 26.19 min and 52.91 (μL/min)/106 cells, respectively.
e
For reference, protein binding of ketoconazole is 98.35%.