Table 5. Plasma and Liver Microsomal Stability, Solubility, Efficiency Metrics, and Mouse Pharmacokinetic Data of Compounds 39 and 50.
| mouse PKg |
|||||||
|---|---|---|---|---|---|---|---|
| compound | plasma t1/2(min)a,c | LM_NADPH t1/2(min)b,c | solubility (μM)d | c Log Pe/LipEf | parameters | i.v.(3 mg/kg) | p.o.(10 mg/kg) |
| 39 | m: >120 (93)h | m: >60 (93)h | <1 | 3.79/3.84 | Cmax[ng/mL] | 701.9 | 296.6 |
| r: >120 (93)h | r: 13 ± 4 | Tmax (min) | 5 | 30 | |||
| h: >60 (83)h | AUC [ng × min/mL] | 20800 | 20748 | ||||
| Vd(L/Kg) | 4.45 | ||||||
| CL (mL/min/Kg) | 144 | ||||||
| F (%) | 30 | ||||||
| 50 | m: >120 (95)h | m: >60 (55)h | >250 | 0.54/6.83 | Cmax[ng/mL] | 5238 | 6872 |
| r: >120 (93)h | r: 48 ± 2 | Tmax (min) | 5 | 15 | |||
| h: >60 (88)h | AUC [ng × min/mL] | 202304 | 407508 | ||||
| Vd(L/Kg) | 0.53 | ||||||
| CL (mL/min/Kg) | 13 | ||||||
| F (%) | 60 | ||||||
a
2.0 μM, 100% mouse or rat plasma (+0.5% DMSO).
b
4.6 μM in mouse, rat or human liver microsomes (LM) with NADPH as a cofactor (0.1% DMSO).
c
Data collected as n ≥ 3.
d
Kinetic solubility (PBS, pH 7.4; n = 3).
e
Calculated with PipelinePilot WebPort 2017.
f
LipE: Lipophilic Efficiency [LipE = pIC50 – c Log P].42
g
Pharmacokinetic parameters of 39 and 50 following intravenous (i.v.) and oral (p.o.) administration to male C57BL/6 mice (n = 3 per time-point).
h
% compound remaining at last time-point.