Table 2.
Selected physicochemical and in vitro ADME profiles and pharmacokinetic analysis of 2 and 13.
|
| ||||||
|---|---|---|---|---|---|---|
| Entry | Biological Stabilitya |
Kinetic Solubilityb |
Thermodynamic Solubilityb |
hERG Inhibitionc | CLint (μL/min/mg
protein)d |
t1/2 (min.) |
|
| ||||||
| 2 (RUC-2) | 97.5 (15 min.) | 35.8 (pH 6.6.) | 41.8 (pH 6.6.) | < 5% @ 25 μM | 0.684 (mouse) | > det. limit (mouse) |
| 93.3 (60 min.) | 34.6 (pH 7.4) | 28.0 (pH 7.4) | 2.83 (rat) | > det. limit (rat) | ||
| 84.5 (120 min.) | 36.1 (pH 8.5) | 46.2 (pH 8.5) | −1.16 (human) | > det. limit (human) | ||
| 43.4 (pH 12) | >400 (pH 12) | |||||
| 13(RUC-4) | 100 (15 min.) | >57.8 (pH 6.6.) | 340.4 (pH 6.6.) | < 5% @ 25 μM | 89.0 (mouse) | 15.6 (mouse) |
| 99.5 (60 min.) | >57.8 (pH 7.4) | 239.5 (pH 7.4) | 54.9 (rat) | 25.3 (rat) | ||
| 91.7 (120 min.) | >57.8 (pH 8.5) | >400 (pH 8.5) | 23.2 (human) | 58.9 (human) | ||
| >57.8 (pH 12) | >400 (pH 12) | |||||
|
| |||||||
|
2 (RUC-2)
Exposure Profile (IP) |
Exposure Profile (IV) |
13 (RUC-4)
Exposure Profile (IP) |
Exposure Profile (IV) | ||||
|
| |||||||
| Av. Weight (g) | 27 | Av. Weight (g) | 27 | Av. Weight (g) | 27 | Av. Weight (g) | 27 |
| Dose (mg) | 0.03 | Dose (mg) | 0.03 | Dose (mg) | 0.03 | Dose (mg) | 0.03 |
| Cmax (μM/mL) | 0.222 | CO (μg/mL) | 1.354 | Cmax (μg/mL) | 0.405 | CO (μg/mL) | 1.145 |
| Tmax (hr) | 0.08 | Tmax (hr) | NA | Tmax (hr) | 0.08 | Tmax (hr) | NA |
| AUC (μg-hr/mL) | 0.045 | AUC (ng-hr/mL) | 0.123 | AUC (μg-hr/mL) | 0.087 | AUC (μg-hr/mL) | 0.137 |
| t1/2(hr) | NA | t1/2 (hr) | 0.07 | t1/2(hr) | NA | t1/2 (hr) | 0.07 |
| % Bioavailabilitye | 36.8% | % Bioavailabilitye | 63.5% | ||||
|
| |||||||
a
Biological Stablity assays were conducted in mouse plasma in triplicate.
b
Kinetic solublity assays were performed in triplicate using both CLND and IHPLC methods (CLND methods are shown). Data was recorded in both (μg/mL and μM (μg/mL is shown).
c
hERG channel inhibition was measured at 0.008 μM, 0.04 μM, 0.2 μM, 1.0 μM, 5.0 μM and 25.0 μM. Values were < 5% at all tested concentrations.
d
Microsomal stability data (hepatocyte data not shown).
e
Data represents measurements from 0 to 0.5 hours.