Table 1. ADME Properties of Lead Compound 7 and 8a.
| property | units | species | 7 | 8 | |
|---|---|---|---|---|---|
| molecular weight | Da | 525.65 | 525.65 | ||
| log D, pH 7.4 | 1.58 | 1.59 | |||
| solubility, pH 7.4 | μM | 86.3 | 199 | ||
| CLint, liver microsomes | μL/min/mg protein | human | 20.6 ± 1.3 | 22.5 ± 0.33 | |
| rat | 13.6 ± 1.2 | 16.4 ± 1.32 | |||
| mouse | 22 ± 0.9 | N.D. | |||
| plasma protein binding | % unbound fraction | human | 22.9 ± 0.8 | 26.8 ± 0.4 | |
| rat | 17.6 ± 0.3 | 17.6 ± 0.4 | |||
| mouse | 8.7 ± 0.9 | N.D. | |||
| plasma stability t1/2 | min | human | >120 | N.D. | |
| Caco-2 permeability A:B | cm s–1 × 10–6 | human | <0.01 | <0.01 | |
| Caco-2 permeability B:A | cm s–1 × 10–6 | human | 9.11 ± 0.62 | 8.38 ± 0.43 | |
| CYP inhibition | 1A2 | μM | human | >50 | >50 |
| 2C9 | 34.15 ± 1.01 | >50 | |||
| 2C19 | 26.19 ± 0.5 | >50 | |||
| 2D6 | 3.64 ± 1.5 | 1.6 ± 0.15 | |||
| 3A4 | 2.35 ± 0.9 | 7.3 ± 1.2 | |||
| hERG currents | μM | >30 | >30 | ||
a
hERG potassium channel currents were determined in quadruplicate, Caco-2 permeability, plasma protein binding, CYP inhibition, and liver microsomal CLint were determined in triplicate, and solubility, log D, plasma stability, and were determined in duplicate. Data are presented as mean ± SD.