Table 5. Pharmacokinetic Profiling of Compounds 1, 7, and 11.
| 1 | 7 | 11 | |
|---|---|---|---|
| GAST MIC (μM) | 0.3 (95 ng/mL) | 0.4 (141 ng/mL) | 0.8 (294 ng/mL) |
| 7H9-ADC MIC (μM) | 0.6 (190 ng/mL) | 0.4 (141 ng/mL) | 0.8 (294 ng/mL) |
| HepG2 IC50 (μM) | >50 | >50 | >50 |
| measured CHI-LogD | 1.8 | 1.5 | 1.6 |
| microsomal clearance (mL/min/g) | mouse 2.3 | mouse 1.4 | mouse 4.8 |
| human <0.5 | |||
| MWa | 317 | 353 | 367 |
| cLogPa/cLogDa | 2.3/2.3 | 2.3/2.3 | 2.7/2.7 |
| TPSAa | 75 | 75 | 75 |
| PAMPA (nm/s) | 83 | 64 | 65 |
| kinetic solubility (μM)b | 83 (free base) | 111 (HCl salt) | >250 |
| C57 mouse PK at 3 iv and 10 po (mg/kg) | free base | HCl salt | free base |
| Cmax (ng/mL) | 748 | 399 | 1112 |
| T1/2 (h) | 1.5 | 1.3 | |
| AUC0–8h (ng·min/mL) | 156 800 | 67 085 | 128 309 |
| Clb (mL/min/kg) | 23 | 39 | |
| Vdss (L/kg) | 0.8 | 1 | |
| % F | 46 | 29 | |
| PPB (% unbound) | 14 | 13 | 21 |
a
Calculated using StarDrop (http://www.optibrium.com).
b
Kinetic aqueous solubility was measured using laser nephelometry of compounds in 2.5% DMSO.