Table 1.
In vitro ADME and anti-VEEV (TC-83 strain) activity of ML336, BDGR-4, BDGR-5, BDGR-69, and BDGR-70.1
| compound | VEEV EC502 (nM) |
VEEV log titer reduction3 |
PBS solubility4 (mg/mL) |
Microsomal stability5, % parent after 1h |
Plasma stability6, % parent after 3h |
plasma protein binding6, % bound at 1 μM / 10 μM |
|---|---|---|---|---|---|---|
| ML336 | 32 ± 5 | 7.0 ± 0.4 | 40.4 | 42.9 | 65.4 | 85.0 / 77.0 |
| BDGR-4 | 47 ± 21 | > 6.2* | 105.6 | 54.5 | 66.4 | 84.3 / 73.7 |
| BDGR-5 | 29 ± 6 | 5.0 ± 1.8 | > 41 | 14.6 | ND | ND |
| BDGR-69 | 28 ± 7 | 7.2 ± 0.7 | > 41 | 27.7 | ND | ND |
| BDGR-70 | 25 ± 8 | 7.0 ± 0.6 | > 41 | 25.1 | ND | ND |
1
None of these compounds showed mammalian cytotoxicity (CC50 > 50 μM, VERO76 cells);
2
50 cytopathic effect (CPE) assay in VERO76 cells;
3
done at 18 h post infection using 5 μM compound concentration in VERO76 cells;
4
kinetic solubility in 1xPBS buffer;
5
mouse microsomes;
6
mouse plasma;
*
No progeny virus plaques were detected. ND = not determined.