Table 5. Pharmacokinetic properties (ADMET) prediction for XL765 and the six proposed dual inhibitors 28, 18, 38, 9, 10, and 19.
| Pharmacokinetic properties (ADMET) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Property | Model Name | Desired value | Unit | XL765 | 28 | 18 | 38 | 9 | 10 | 19 |
| ABSORPTION | Water solubility | log mol/L | -3.49 | -4.40 | -3.31 | -4.07 | -4.41 | -3.32 | -3.31 | |
| Caco2 permeability | >0.90 | log Papp in 10–6 cm/s | 0.37 | 0.47 | 0.42 | 0.22 | 0.16 | 0.39 | 0.45 | |
| Intestinal absorption (human) | >>30 | % Absorbed | 100 | 100 | 90.49 | 80.08 | 96.11 | 89.09 | 82.79 | |
| Skin Permeability | >-2.5 | log Kp | -2.73 | -2.73 | -2.73 | -2.73 | -2.73 | -2.73 | -2.73 | |
| P-glycoprotein substrate | No | Yes/No | No | Yes | Yes | Yes | Yes | Yes | Yes | |
| P-glycoprotein I inhibitor | Yes/No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | ||
| P-glycoprotein II inhibitor | Yes/No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | ||
| DISTRIBUTION | VDss (human) | 0.71<VDss<2.81 | log L/kg | -1.56 | -0.82 | -0.90 | -0.61 | -0.79 | -0.65 | -0.61 |
| Fraction unbound (human) | Fu | 0.14 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| BBB permeability | <0.3 | log BB | -1.62 | -0.42 | -1.45 | -1.39 | -0.44 | -1.51 | -1.32 | |
| CNS permeability | >-2 | log PS | -3.42 | -3.32 | -3.47 | -3.38 | -3.32 | -3.62 | -2.83 | |
| METABOLISM | CYP2D6 substrate | No | Yes/No | No | No | No | No | No | No | No |
| CYP3A4 substrate | No | Yes/No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |
| CYP1A2 inhibitor | Yes/No | No | No | No | No | No | No | No | ||
| CYP2C19 inhibitor | Yes/No | No | Yes | No | Yes | Yes | No | No | ||
| CYP2C9 inhibitor | Yes/No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | ||
| CYP2D6 inhibitor | Yes/No | No | No | No | No | No | No | No | ||
| CYP3A4 inhibitor | Yes/No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | ||
| EXCRETION | Total Clearance | log ml/min/kg | 0.03 | -0.18 | 0.18 | -0.13 | 0.36 | 0.07 | -0.12 | |
| Renal OCT2 substrate | No | Yes/No | No | No | No | No | No | No | No | |
| TOXICITY | AMES toxicity | No | Yes/No | No | No | No | No | No | No | No |
| Max. tolerated dose (human) | <0.477 | log mg/kg/day | 0.34 | 0.22 | 0.52 | 0.33 | 0.18 | 0.56 | 0.56 | |
| hERG I inhibitor | No | Yes/No | No | No | No | No | No | No | No | |
| hERG II inhibitor | No | Yes/No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |
| Oral Rat Acute Toxicity (LD50) | mol/kg | 3.16 | 2.68 | 2.73 | 2.80 | 2.66 | 2.71 | 2.53 | ||
| Oral Rat Chronic Toxicity (LOAEL) | log mg/kg_bw/day | 2.14 | 1.65 | 2.75 | 1.88 | 1.68 | 2.72 | 2.58 | ||
| Hepatotoxicity | No | Yes/No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |
| Skin Sensitization | No | Yes/No | No | No | No | No | No | No | No | |
| T. pyriformis toxicity | <-0.5 | log ug/L | 0.28 | 0.28 | 0.28 | 0.28 | 0.28 | 0.28 | 0.28 | |
| Minnow toxicity | >-0.3 | log mM | 0.52 | 0.91 | 0.83 | -0.10 | 0.09 | 1.56 | 0.99 | |
ADMET, absorption, distribution, metabolism, excretion, and toxicity; BBB, blood‐brain barrier; CNS, central nervous system; CYP, cytochrome P; hERG, human ether-a-go-go-related gene; LD50, lethal dose 50%; LOAEL, lowest observed adverse effect level; OCT2, organic cation transporter 2; VDss, steady-state volume of distribution.