Table 1.
Evaluation of Comparator Compounds on DHFR Inhibition, Kinetic Solubility, Clearance in Human Liver Microsomes and MDR1-MDCK Permeability
| Compound | TgDHFRa IC50 (nM) | hDHFRa IC50 (nM) | Selectivity Indexb | Solubilityc (μM) | HLM (mL/min/kg) | MDR1-MDCKd |
|---|---|---|---|---|---|---|
| 1 | 139 ± 14 | 1680 ± 230 | 12 | 184 | <8.6 | 36 (0.83) |
| 2 | 8.76 ± 1.0 | 689 ± 39 | 79 | 3.9 | 28.4 | 2.7 (0.62) |
| 4 | 33,100 ± 3400 | 503,000 ± 51,000 | 15 | -- | <8.6 | 7.5 (3.5) |
| 5 | 78.3 ± 6.7 | 4.74 ± 0.36 | 0.061 | -- | -- | -- |
| 6 | 1.35 ± 0.07 | 4.07 ± 0.11 | 3.0 | -- | -- | -- |
a
Average of at least 3 independent replicates ± SEM.
b
Selectivity index (SI) is the hDHFR IC50/TgDHFR IC50, determined within the same experiment.
c
Kinetic solubility.
d
A:B (papp 10−6 cm/sec) (ER), where ER is efflux ratio defined as permeability in A:B/B:A directions.