Table 1. In Vitro and In Vivo Profile of Compound 4.
| in vitro profile | |
|---|---|
| INMAC pEC50a,b | 6.2 |
| THP-1 cells pEC50a,b | <4.3 |
| aqueous solubility (μM)c | 150 |
| FaSSIF solubility (μM)a | 15 |
| CLi mL/min/ga,d | <0.5 |
| in vivo profilee | ||
|---|---|---|
| iv PK (3 mg/kg) | T1/2 (h) | 0.5 |
| AUC ng·min/mL | 135,000 | |
| Clb mL/min/Kg | 22 | |
| po PK (10 mg/kg) | Cmax (ng/mL) | 1300 |
| Tmax (h) | 0.5 | |
| AUC ng·min/mL | 258,000 | |
| Vdss L/kg | 0.8 | |
| F % | 57 | |
| % reduction in parasitemiaf | 98 | |
a
Data reported previously.10
b
INMAC is the intramacrophage assay carried out in THP-1 cells with L. donovani amastigotes. Data are the result of five independent replicates and standard deviations are ≤0.2.
c
Aqueous solubility is kinetic solubility measured by CLND.
d
Cli is the mouse liver microsomal intrinsic clearance.
e
Mouse PK studies dosed at 10 mg/kg po and 3 mg/kg iv.
f
Infected mouse model of VL, dosed at 50 mg/kg ip, b.i.d for 5 days.