Table 4.
Calculated ADMET descriptors related to metabolism, excretion and toxicity properties. The most promising amidine-containing derivative 15 has been highlighted in yellow, as well as the reference compounds β-PEA and RO5263397. The other most interesting analogues, 2, 6, 9 and 16, are shown in light cyan.
| Comp. | hERG Inhibitor | Endocrine System Disruption a | CYP3A4 and CYP2D6 | |||
|---|---|---|---|---|---|---|
| Inhibitor | Reliability Index (R.I.) | LogRBA > −3 (R.I. ≥ 0.3) |
LogRBA > 0 (R.I. ≥ 0.3) |
Inhibitor < 10 mM (R.I. > 0.3) |
Substrate (R.I. ≥ 0.3) |
|
| β-PEA | 0.06 | 0.40 | No binder | No binder | 0.02 | >50% |
| 1 | 0.07 | 0.34 | No binder | No binder | 0.01 | >50% |
| 2 | 0.08 | 0.35 | No binder | No binder | 0.01 | >50% |
| 3 | 0.11 | 0.29 | No binder | No binder | 0.01 | >50% |
| 4 | 0.11 | 0.29 | No binder | No binder | 0.01 | >50% |
| 5 | 0.15 | 0.29 | No binder | No binder | 0.01 | >50% |
| 6 | 0.10 | 0.29 | No binder | No binder | 0.02 | >50% |
| 7 | 0.09 | 0.29 | No binder | No binder | 0.02 | >50% |
| 8 | 0.15 | 0.22 | No binder | No binder | 0.02 | >50% |
| 9 | 0.43 | 0.56 | No binder | No binder | 0.01 | >50% |
| 10 | 0.07 | 0.35 | No binder | No binder | 0.01 | >50% |
| 11 | 0.05 | 0.33 | No binder | No binder | 0.02 | >50% |
| 12 | 0.07 | 0.30 | No binder | No binder | 0.01 | >50% |
| 13 | 0.12 | 0.25 | No binder | No binder | 0.01 | >50% |
| 14 | 0.14 | 0.27 | No binder | No binder | 0.01 | >50% |
| 15 | 0.21 | 0.24 | No binder | No binder | 0.01 | >50% |
| 16 | 0.27 | 0.30 | No binder | No binder | 0.01 | >50% |
| RO5263397 | 0.06 | 0.36 | No binder | No binder | 0.01 | 33% |
a RBA: relative binding affinity with respect to that of estradiol. Compounds showing LogRBA > 0 are classified as strong estrogen binders, while those showing LogRBA < −3 are considered as non-binders. (RI: reliability index. Borderline-allowed values for reliability parameter are ≥ 0.3; the most predictive fall in the range 0.50–1.0).