Table 3.
ADMET Properties of 29, 34, 35, 36
| Compound | 29 | 34 | 35 | 36 | |
|---|---|---|---|---|---|
| Protein plasma binding (% bound) at 1 μMa | human | 71 | 98.1 | 91.7 | 96.5 |
| mouse | 64 | 95.5 | 89 | 91.4 | |
| rat | 78 | 97 | 92.4 | 96 | |
| Human cytochrome P450 inhibition at 10μM (%)a | CYP3A4 | 4 | −28 | −13 | −22 |
| CYP2D6 | 20 | 9 | −40 | 1 | |
| CYP2C9 | −6 | −13 | −11 | −18 | |
| CYP1A2 | 5 | 13 | 10 | 20 | |
| Ion channel % Inhibition at 10 μMa,b |
Voltage-gated sodium (Nav1.5) | 32 | 72 | ||
| hERG | 35 | 77 | 19 | 6 | |
| Voltage-gated calcium (Cav1.2) | <25 | 28 | ND | ND | |
| Inward-rectifying voltage-gated potassium (Kir2.1) | <25 | <25 | ND | ND | |
| Hyperpolarization-activated cyclic nucleotide-gated potassium (HCN4) | <25 | <25 | ND | ND | |
| Caco-2 cells | A-B (10−6 cm/s) | 26.2 | ND | ND | ND |
| Efflux ratio | 1.0 | ND | ND | ND |
ND = No data. A-B = movement of the compound from the apical to the basal side of the membrane; a surrogate for permeability
a
Further details for the assays can be found in the experimental section and reference 37.
b
Compounds were profiled in the Eurofin cardiac profiler panel. Further details can be found in the supporting information.