Table 2.
DAQ's and DAQM's hERG, ADME and PK.
| DAQ | DAQM | Controls | ||
|---|---|---|---|---|
| hERG inhibition (IC50) | CQ | Cisapride | ||
| QPatch (2 different cells, fitting curve – Report S2) | 7.3 μM | 12.2 μM | 12.1 μM | 0.02 μM |
| Fluorescence polarization | 7.0 μM | 5.3 μM | 7.5 μM | – |
| CYP inhibition panel (IC50)a | >10 μM | NTb | – | |
| Thermodynamic solubility (PBS, pH 7.4) | 1210 ± 0.02 μM | 1350 ± 0.02 μM | – | |
| Permeability (Caco2) | Atelonol | Metoprolol | ||
| PappA-B | (15 ± 0.07) x 10-6 cm/s | (14 ± 0.06) x 10-6 cm/s | (0.26 ± 0.07) x 10-6 cm/s | (35 ± 0.07) x 10-6 cm/s |
| PappB-A | (11 ± 0.05) x 10-6 cm/s | (11 ± 0.09) x 10-6 cm/s | (0.57 ± 0.05) x 10-6 cm/s | (29 ± 0.01) x 10-6 cm/s |
| Plasma stability (t = 0–60min) | >60 minc | 158.7 min | – | |
| Plasma protein binding (PPB) | Warfarin | Quinidine | ||
| PPB mouse | 76.4% | 84.5% | 95.1% | 82.7% |
| PPB human | 97.5% | NT | 99.4% | 92.2% |
| DAQ's abundance in hepatocytes after 30min | ||||
| Mouse | <15% | NT | – | |
| Monkey | 39% | NT | – | |
| Human | 55% | NT | – | |
| Clearance (Clint) in liver microsomes (LM) | Ketanserin | |||
| mouse (MLM) | 2741 mL/min/kg | 273 mL/min/kg | 445 mL/min/kg | |
| human (HLM) | 159 mL/min/kg | 8 mL/min/kg | 52 mL/min/kg | |
| PK (t1/2, mice) | ||||
| PO | 2.1 h | 4.7 h | – | |
| IV | 2.9 h | 4.8 h | – | |
ADME assays by ChemPartner performed in duplicates.
a
CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4.
b
NT: Not Tested.
c
% of remaining DAQ was near 100% at t = 60 min.