Table 6.
In silico ADMET predictions of the potential inhibitors 7a-e.
| Property and Model Name | 7a | 7b | 7c | 7d | 7e | MLN-4760 |
|---|---|---|---|---|---|---|
| Absorption | ||||||
| Water solubility (log mol/L) | −2.965 | −2.972 | −2.958 | −2.957 | −2.945 | −2.892 |
| Caco2 permeability (log Papp in 10−6 cm/s) | 1.251 | 1.252 | 1.262 | 1.415 | 1.267 | 0.744 |
| Intestinal absorption in humans (% Ab) | 92.92 | 93.184 | 93.046 | 92.44 | 91.216 | 44.856 |
| Skin permeability (log Kp) | −2.736 | −2.736 | −2.736 | −2.74 | −2.741 | −2.735 |
| P-glycoprotein substrate (Yes/No) | Yes | Yes | Yes | Yes | Yes | Yes |
| P-glycoprotein I inhibitor (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| P-glycoprotein II inhibitor (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| Distribution | ||||||
| VDss in humans (log L/kg) | 0.065 | 0.118 | 0.198 | 0.209 | 0.173 | 0.011 |
| Fraction unbound in humans (Fu) | 0.079 | 0.075 | 0.071 | 0.087 | 0.091 | 0.381 |
| BBB permeability (log BB) | −0.945 | −0.976 | −1.002 | 0.555 | 0.323 | −1.403 |
| CNS permeability (log PS) | −1.887 | −1.886 | −1.876 | −1.294 | −1.848 | −3.238 |
| Metabolism | ||||||
| CYP2D6 substrate (Yes/No) | No | No | No | No | No | No |
| CYP3A4 substrate (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| CYP1A2 inhibitor (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| CYP2C19 inhibitor (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| CYP2C9 inhibitor (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| CYP2D6 inhibitor (Yes/No) | No | No | No | Yes | No | No |
| CYP3A4 inhibitor (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| Excretion | ||||||
| Total Clearance (log ml/min/kg) | 0.252 | 0.182 | 0.212 | 0.406 | 0.431 | −0.144 |
| Renal OCT2 Substrate (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| Toxicity | ||||||
| AMES toxicity (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| Max. tolerated dose in humans (log mg/kg/day) | 0.372 | 0.374 | 0.366 | 0.425 | 0.422 | 0.438 |
| hERG I inhibitor (Yes/No) | No | No | No | No | No | No |
| hERG II inhibitor (Yes/No) | Yes | Yes | Yes | Yes | Yes | No |
| Oral Rat Acute Toxicity (LD50) (mol/kg) | 2.573 | 2.569 | 2.564 | 2.805 | 2.793 | 2.482 |
| Oral Rat Chronic Toxicity (LOAEL) (log mg/ky_bw/day) | 1.236 | 1.257 | 1.304 | 0.951 | 1.083 | 2.35 |
| Hepatotoxicity (Yes/No) | No | No | No | No | No | Yes |
| Skin sensitization (Yes/No) | No | No | No | No | No | No |
| T. Pyriformis toxicity (log ug/L) | 0.285 | 0.285 | 0.285 | 0.285 | 0.285 | 0.285 |
| Minnow toxicity (log mM) | 0.342 | 0.19 | 0.183 | 0.097 | 0.756 | 0.635 |