Table 3. Physicochemical and metabolism parameters for NCL812, NCL195 and NCL219 in human and mouse liver microsomes.
| Properties | Compound | |||||
|---|---|---|---|---|---|---|
| NCL812 | NCL195 | NCL219 | ||||
| Physicochemical Parameters | ||||||
| Mol Wta | 334.20 | 359.43 | 405.59 | |||
| PSAa (Å2) | 72.6 | 100.6 | 72.6 | |||
| FRBa | 4 | 6 | 6 | |||
| H-Bond Donora | HBD = 3 | HBA = 6 | HBD = 4 | HBA = 7 | HBD = 3 | HBA = 5 |
| pKaa | 5.0; imine (italics) | 1.2; amine (bold) | 4.9 / 4.3; amine (italics) | 2.2; pyrimidine (bold) | 5.2; imine (bold) | 2.2 amine (italics) |
| LogDpH 7. 4b | 4.5 | 4.5 | >5.3d | |||
| Solubilityc (μg/ml) | pH 2.0 = 6.3–12.5 | pH 6.5 = <1.6 | pH 2.0 = 3.1–6.3 | pH 6.5 = <1.6 | pH 2.0 = 0.78–1.6 | pH 6.5 = 0.78–1.6 |
| Metabolism parameters | ||||||
| Species | Human | Mouse | Human | Mouse | Human | Mouse |
| T1/2 (min) | >247 | >247 | >247 | >247 | 18 | 14 |
| CLINT (μl/min/mg protein) | <7 | <7 | <7 | <7 | 94 | 121 |
| Predicted CLblood (ml/min/kg) | <5 | <16 | <5 | <16 | 16 | 87 |
| Predicted EH | <0.22 | <0.13 | <0.22 | <0.13 | 0.79 | 0.72 |
a Calculated using ChemAxon (JChem for Excel).
b Estimated using a gradient HPLC chromatographic method.
c Kinetic solubility estimated via nephelometry.
d the retention times were greater than the most lipophilic standard compound, therefore LogD values are reported as > 5.3.
Mol Wt = molecular weight; PSA = polar surface area; HBD/HBA = hydrogen bond donor / acceptor; pKa is colour coded to the atoms highlighted in each structure. Clint = in-vitro intrinsic clearance; EH = predicted in-vivo hepatic extraction ratio.