In vitro safety and biochemical profile of KR-26827 and 6d.
| In vitro assay | KR-26827 | 6d |
|---|---|---|
| CYP inhibition (IC50, μM) a | ||
| 1A2 | 8.3 | 21.5 |
| 2C9 | 2.0 | 2.6 |
| 2C19 | 14.3 | 25.8 |
| 2D6 | 16.9 | >100 |
| 3A4 | 12.1 | 23.4 |
| Cardiotoxicity (% inhibition, 10 μM) b | ||
| hERG | 43.5 | 19.2 |
| Cytotoxicity assay (IC50, μM) c | ||
| VERO | 40.0 | >100 |
| HFL-1 | 43.7 | >100 |
| L929 | 39.2 | >100 |
| NIH 3T3 | 33.0 | >100 |
| CHO-K1 | 36.5 | >100 |
| Liver microsomal phase I stability (%) d | ||
| Mouse | naf | 74.5 |
| Rat | naf | 41.6 |
| Human | naf | 93.0 |
| Plasma protein binding (%) e | ||
| Mouse | naf | 99.92 |
| Human | naf | 98.16 |
a
CYP inhibition in human liver microsomes using cocktail substrate assay.
b
hERG ligand binding assay % inhibition at 10 μM concentration.
c
The IC50 in various mammalian cell lines; (VERO: African green monkey kidney cell line, HFL-1: human embryonic lung cell line; L929: NCTC clone 929 mouse fibroblast cell line; NIH 3T3: mouse embryonic fibroblast cell line, CHO-K1: Chinese hamster ovary cell line).
d
Liver microsomal phase I stability (%) remaining after 30 min.
e
Plasma protein binding rate (%) remaining after 4 h incubation at 37 °C.
f
na: not applicable. Assay conditions are described in ESI.†