Table 3. In Vitro Profiles of Compound 2.
| X1 | X2 | X3 | R | hNaV1.1 IC50 (μM)a | hNaV1.5 IC50 (μM)a | hNaV1.7 IC50 (μM)a | mNaV1.7 IC50 (μM)a | hERG inhibition at 100 μMa,b | Log Dc | Solubility (μM)d | Mouse PB free (%)d | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2a | H | H | H | c-Pr | >100 | >300 | 1.6 | >10 | –8.8 ± 3.1 | NTe | NTe | NTf |
| 2b | H | H | H | Me | NTf | >300 | >10 | NTf | –0.1 ± 11.6 | NTe | NTe | NTf |
| 2c | H | F | H | c-Pr | >100 | >300 | 0.86 | 2.7 | –1.1 ± 5.8 | NTe | NTe | NTf |
| 2d | H | Cl | H | c-Pr | 9.9 | 107 | 0.085 | 0.46 | 34.1 ± 2.1 | 0.80 | 35 | NTf |
| 2e | H | CF3 | H | c-Pr | 6.6 | 14 | 0.015 | 0.061 | 6.9 ± 9.0 | 1.0 | 130 | 0.50 |
| 2f | CF3 | H | H | c-Pr | >100 | 210 | 0.059 | 1.6 | 21.0 ± 16.3 | 1.0 | 29 | 1.4 |
| 2g | H | CF3 | F | c-Pr | 1.2 | 32 | 0.040 | 0.015 | –2.9 ± 0.0 | 0.60 | 25 | 0.7 |
a
Data were obtained with a high-throughput electrophysiology system (IonWorks Quattro). Values are from a single experiment run in quadruplicate.
b
hERG inhibitory activity at 10, 30, and 100 μM was assessed, and the dose response was confirmed. Each value represents the mean ± SD.
c
Distribution coefficients (log D) were measured after partition between 1-octanol and PBS (pH = 7.4).
d
Unbound fractions (%) in mouse plasma.
e
Aqueous thermodynamic solubility at pH 6.8.
f
Not tested.