Table 4. In Vitro Antimalarial and ADME-Tox Data, Physicochemical Parameters, and In Vivo PK Data for 7e·HCl.
| Entry | Assay | Value |
|---|---|---|
| 1 | Dd2 EC5072h (nM)a,b | 108 ± 7 |
| 2 | 3D7 EC5072h (nM)a,c | 53 ± 7 |
| 3 | Dd2-KAE609R EC5072h (nM)a,d | 101 ± 5 |
| 4 | W2 EC5072h (nM)a,e | 100 ± 8 |
| 5 | 4G EC5072h (nM)a,f | 110 ± 17 |
| 6 | 3D7 3H–H IC5048h (nM)g | 70 ± 10 |
| 7 | 3D7 LDH IC5072h (nM)h | 117 ± 11 |
| 8 | HEK293 CC50 (nM) | 32,000 ± 4,000 |
| 9 | hPHep CC5096h (nM)i | 8,500 ± 1,900 |
| 10 | E. coli MIC (nM) | >250,000 |
| 11 | hERG IC50 (nM) | 510 |
| 12 | Mini-Ames Panel | negative |
| 13 | MW (g/mol, free base) | 427 |
| 14 | tPSA (Å2) | 65.5 |
| 15 | Log D (pH 7.4)j | 3.3 |
| 16 | PBS Solubility (μM, pH 7.4) | 9.5 |
| 17 | PPB (mouse) | 99.49% |
| 18 | Mouse plasma stability | 100% at 1 h |
| 19 | Mouse microsomal t1/2 (min) | 110 |
| 20 | Clint (mouse μg/mL/min) | 12.6 |
| 21 | %F (rat)k | 40% |
| 22 | Cmax (nM, oral 40 mg/kg, rat)k | 800 ± 25 |
| 23 | Rat plasma t1/2 (h)k | 8 |
| 24 | Vdss (L/kg, rat)k | 21.8 |
a
Growth inhibition determined using the SYBR Green I assay for all EC50 determinations. Values represent average ± SEM from at least three independent biological replicates.
b
Resistant to chloroquine (CQ), pyrimethamine (PY), and mefloquine (MQ).
c
Sensitive to CQ, PY, and MQ.
d
KAE609-resistant strain, courtesy of E. Winzeler.
e
Resistant to CQ, quinine, PY, cycloguanil, and sulfadoxine.
f
Dihydroartemisinin- and CQ-resistant field strain, courtesy of D. E. Kyle.
g
[3H]hypoxanthine incorporation assay.
h
Lactate dehydrogenase activity.
i
Primary human hepatocytes.
j
Experimentally determined.
k
See Supporting Information for details.