Table 3.
Comparisons of tipifarnib, compound 2 racemic mixture, enantiomers of compound 2, and posaconazole
| Assay | Tipifarnib | Compound 2 racemic mixture | Enantiomer 2.1 | Enantiomer 2.2 | Posaconazole |
|---|---|---|---|---|---|
| T. cruzi amastigote; EC50 (μM) | 0.006 | 0.0005 | 0.00031 | 0.0263 | 0.00016 |
| Rat PFT; IC50 (μM) | 0.0013 | 0.991 | |||
| T. cruzi CYP51 binding; Kd (μM)a | 0.11 | 0.18 | 3.8 | 0.06 | |
| Liver microsome stability; t1/2 (min) | |||||
| Human | 100 | 270 | >360 | ||
| Mouse | >180 | 28 | >180 | ||
| CYP450 inhibition (μM) | |||||
| CYP1A2 | 13.3 | >30 | >39 | ||
| CYP2C9 | 0.29 | 0.08 | 9.5 | ||
| CYP2C19 | 4.2 | 3.2 | 20.9 | ||
| CYP2D6 | 6.5 | 25 | >30 | ||
| CYP3A4/5 midazolam | 2.3 | 0.65 | 0.09 | ||
| CYP3A4/5 testosterone | 2.1 | 0.9 | 0.04 |
a
The apparent Kds were calculated by plotting T. cruzi CYP51 spectral responses (ΔA420–390) against free ligand concentration (15).