Table 3. Summary of Key in Vitro and in Vivo ADME Properties for Representative Compounds.
| analog | bioc IC50 (nM)a | cell IC50 (nM)b | RLM, HLM (mL min–1 kg–1) | MDCK-MDR1cPapp/ER | RPPB/HPPB (fu) | Cl/Clu (L h–1 kg–1)d | rat Kp,uue | CYP3A4/2C9,f IC50 (μM) | hERG IC50 (μM) |
|---|---|---|---|---|---|---|---|---|---|
| 8 | 3.9 | 90 | <11, 14 | 1.7/15 | 39/40 | 1.6/4.0 | >10/10 | 30 | |
| 11 | 2.4 | 93 | 72, 9 | 10/2.2 | 8/13 | 3.4/42 | 0.61 | 5.9/0.7 | 15 |
| 21 | 21 | 138 | <11, 6 | 5.0/5.0 | 5.3/5.4 | 0.36/6.7 | 0.38 | 8.8/>10 | >30 |
a
Biochemical assay.
b
Inhibition of ASK1 autophosphorylation. IC50 results are the geometric mean of a minimum of two determinations.
c
MDCK-MDR1 human P-gp transfected cell line. Papp = apparent permeability, apical-to-basolateral (10–6 cm/s); ER = (B–A)/(A–B) efflux ratio.
d
Clu=Cl/fu.
e
DMA/EtOH/PG/water (1:1:3:5) was used as the vehicle.
f
Midazolam and tolbutamide were used as substrates.