Table 3.
In Vitro and In Vivo Experimental Pharmacokinetic Parameters of Compounds 18 and 39
| test | reference compound(s) | compound 18 | compound 39 |
|---|---|---|---|
| simul. intestinal fluid % remaining at 120 min (t1/2, min) | Verapamil 100 (>240) | 100 (573) | 86.2 (533) |
| simul. gastric fluid % remaining at 120 min t1/2, min) | Omeprazole 0.0 (15.3) | 69.1 (204) | 99.7 (>240) |
| plasma stability % remaining at 120 min t1/2, min, 3 species) | 0.0 (0.11, h, procaine); 83.9 (414, r, diltiazem); 0.0 (0.11, m, procaine) |
69.7 (159, h); 88.7 (580, r); 83.5 (695, m) |
53.2 (140, h); ~ 100 (>240, r); ~ 100 (>240, m); |
| CYP1A2, IC50 (μM) | Miconazole, 4.55 | 6.99 | 1.31 |
| CYP2C9, IC50 (μM) | Miconazole, 0.38 | >30 | 32.3 |
| CYP2C19, IC50 (μM) | Miconazole, 0.00002 | >30 | 83.6 |
| CYP2D6, IC50 (μM) | Miconazole, 1.64 | >30 | 60.8 |
| CYP3A4 (IC50, μM) | Miconazole (0.0010) | >30 | 61.6 |
| microsomal stability % remaining at 120 min (t1/2, min, 3 species) | Testosterone 5.44 (15.6, h); 0 (1.43, r); 0 (4.33, m) |
81.2 (200, h); 52.1 (70, r); 76.4 (194, m) | 92.1 (>120, h); 86.3 (>120, r); 75.2 (>120, m); |
| plasma protein binding % bound (3 species) | Warfarin, 96.3 (h); 100 (r); 83.6 (m) | ~100 (h);99.1 (r);~100 (m) | 93.6 (h);100 (r); 100 (m) |
| hERG, IC50 (μM)a | n/a | 6.06 | >30b |
| HepG2 cell toxicity, IC50 (μM) | Verapamil, 65.2 | >30 | 35.4 |
| aqueous solubility pH 7.4 (μg/mL) | n/a | 0.39 | <0.01 |
| oral bioavailability, t1/2 (h) (3 mg/kg, p.o.) | n/a | 28.7%F, 1.29 | 64.0%F, 3.44 |
a
Fluorescence polarization hERG assay.
b
27% inhibition at 30 μM.