Table 7. Further in Vitro Characterization of 27.
| permeability assays | |||
|---|---|---|---|
| cell line | Papp (A-B) (cm/s) | Papp (B-A) (cm/s) | efflux ratio |
| MDCK-MDR1 | 6.2 × 10–6 | 7.2 × 10–6 | 1.2 |
| Caco-2 | 6.5 × 10–6 | 7.9 × 10–6 | 1.2 |
| definitive P450 inhibition assaysa | ||
|---|---|---|
| P450 | probe | IC50 (μM) |
| CYP3A4 | midazolam | 133 ± 23 |
| CYP3A4 | testosterone | >200 |
| CYP2D6 | (R)-bufuralol | >200 |
| CYP2C9 | diclofenac | 29.9 ± 7.3 |
| CYP2C19 | (S)-mephenytoin | 106 ± 10 |
| CYP2C8 | amodiaquine | >200 |
| CYP2B6 | efavirenz | >200 |
| CYP1A2 | phenacetin | 2.90 ± 0.72 |
| stability in human cryopreserved hepatocytes | |
|---|---|
| intrinsic clearance (CLINT) | 1.43 μL/min/million cells |
| half-life (t1/2) | 322 min |
| predicted hepatic clearance (CLHEP) | 3.59 mL/min/kg |
| cardiac
ion channel panelb | |||
|---|---|---|---|
| ion channel | IC50 (μM) | ion channel | IC50 (μM) |
| hERG | 73.6 | hCav1.2 | >100 |
| hNav1.5 (tonic) | >100 | hCav3.2 | >100 |
| hNav1.5 (phasic) | >100 | hKir2.1 | >100 |
| hKv4.3 | >100 | hHCN2 | >100 |
| hKv1.5 | >100 | hHCN4 | >100 |
| bacterial
reverse mutation assayc | ||||
|---|---|---|---|---|
| TA98 | TA100 | WP2 uvrA | TA135 | TA1537 |
| negative | negative | negative | negative | negative |
a
Assayed in pooled HLM (with and without NADPH) using CYP-specific probe substrates.
b
Evaluated using IonWorks Quattro system.
c
With and without S9 metabolic activation.