Table 4.
In Vitro ADMET Values for P2Y 14 R Antagonist 15 in This Study, Compared to Reference Antagonist 2b a
| test | 2bb | 15 |
|---|---|---|
| simulated intestinal fluid (% remaining at 120 min) | 99.1 | 93.3 |
| simulated gastric fluid (% remaining at 120 min) | 100a | 69.8 |
| CYP1A2 (IC50, μM) | >30 | >30 |
| CYP2C9 (IC50, μM) | >30 | >30 |
| CYP2C19 (IC50, μM) | >30 | >30 |
| CYP2D6 (IC50, μM) | >30 | >30 |
| CYP3A4 (IC50, μM) | >30 | >30 |
| plasma stability (3 species)c(% remaining at 120 min) | 82.8 (r); 100 (m) | 81.3 (r); 100 (m); 91.1 (h) |
| microsomal stability (t1/2, min) | 243 (m), 91.0 (r), 280 (h) | 355 (m), 342 (r), >400 (h) |
| hERG, IC50 (μM) | >30 | >30 |
| hepG2 (human hepatoma) cell toxicity, IC50 (μM)a | 11.0 | 32.6 ± 5.0 |
| plasma protein binding (3 species, % bound) | 99.76 (m), 99.79 (r), 87.98 (h) | 99.86 (m), 99.48 (r), 99.30 (h) |
| solubility, (μg/mL) | 1.90 (pH 7.4)d | 7.1 ± 0.4 (pH 4.0), 1.4 ± 0.1 (pH = 7.4)e |
a
Procedures are described in Jung et al.17 hERG inhibition was measured using a fluorescent dye binding method (Supporting Information).
b
Data determined in Wen et al.5
c
Species tested for plasma stability were human, rat, and mouse; species as indicated for microsomal stability.
d
Mean ± standard deviation (SD), pION method, determined by Jai Research Foundation (JRF) India of JRF Global (Gujarat, India).
e
Mean ± SD, pION method, determined at NIH.