Table 4.
Molecular and pharmacokinetic properties of AGP and hit AGP analogs
| Properties | AGP | Ana1 | Ana2 | Ana3 | Ana4 | Ana5 |
|---|---|---|---|---|---|---|
| MW | 350.45 | 410.52 | 390.51 | 388.42 | 388.42 | 404.46 |
| H-bond acceptors | 5 | 6 | 5 | 7 | 7 | 7 |
| H-bond donors | 3 | 1 | 1 | 2 | 2 | 2 |
| TPSA | 86.99 | 101.27 | 64.99 | 66.76 | 66.76 | 66.76 |
| Consensus Log P | 2.30 | 2.94 | 3.56 | 3.54 | 3.54 | 4.14 |
| Lipinski #violations | Yes; 0 | Yes; 0 | Yes; 0 | Yes; 0 | Yes; 0 | Yes; 0 |
| Water solubility | Soluble | Soluble | Moderately soluble | Soluble | Soluble | Moderately soluble |
| GI absorption | High | High | High | High | High | High |
| Human oral bioavailability | No | No | No | Yes | Yes | Yes |
| P-glycoprotein inhibitor | No | No | No | No | No | No |
| BBB permeation | No | No | Yes | Yes | Yes | No |
| VD (0.04–20 L/kg: excellent) | 0.612 | 0.884 | 1.457 | 0.784 | 0.784 | 0.87 |
| CYP inhibitor | No | No | No | No | No | No |
|
CL (≥ 5: excellent) ml/min/kg |
8.907 | 9.827 | 13.293 | 13.682 | 13.682 | 10.480 |
| T1/2 (0–0.3: excellent) | 0.249 | 0.082 | 0.096 | 0.041 | 0.041 | 0.034 |
| Acute oral Toxicity (c) | III | III | III | III | III | III |
| Carcinogenicity | No | No | No | No | No | No |
| Hepatotoxicity | No | No | No | No | No | No |
| Human either-a-go-go inhibition | No | Yes | Yes | No | No | No |
| Ames mutagenesis | No | No | No | No | No | No |
| Avian toxicity | No | No | No | No | No | No |
| Predicted LD50 | 1890 mg/kg | 400 mg/kg | 590 mg/kg | 400 mg/kg | 400 mg/kg | 1890 mg/kg |
| Predicted Toxicity Class | 4 | 4 | 4 | 4 | 4 | 4 |
CL clearance of a drug, Consensus Log P arithmetic mean of the five predictive values (XLOGP3, WLOGP, MLOGP Silicos-IT Log P, and iLOGP), CYP cytochrome, GI gastro intestinal, H-bond hydrogen bond, LD50 lethal dose at which 50% of test subjects die upon exposure to a compound, MW molecular weight, TPSA topological polar surface area, T1/2 half-life, VD volume distribution