Table 2.
Physicochemical, drug-like, and in vitro ADME properties of investigated and reference MAO-B inhibitors.
| Compound | MW | pIC50 | Stability | tPSAa | %ABS | HBA/Da | logBBa | logS7.4 | logD7.4 | LLE |
|---|---|---|---|---|---|---|---|---|---|---|
| NTZ-1006 | 306.15 | 9.23 | Stable | 57.78 | 89.07 | 4/1 | 0.065 | n.d. (−4.56a) | n.d. (3.73a) | 5.50 |
| NTZ-1032 | 289.04 | 9.17 | Stable | 57.78 | 89.07 | 4/2 | 0.030 | n.d. (−4.48a) | n.d. (3.00a) | 6.17 |
| NTZ-1034 | 273.24 | 8.80 | Stable | 57.78 | 89.07 | 4/2 | −0.002 | −4.22 (−4.61a) | 2.04 (2.40a) | 6.76 |
| NTZ-1091 | 320.17 | 9.41 | Stable | 46.92 | 92.81 | 4/2 | 0.246 | −4.75 (−4.82a) | 3.24 (3.76a) | 6.17 |
| NTZ-1441 | 303.06 | 9.18 | Stable | 46.92 | 92.81 | 4/2 | 0.216 | −3.87 (−4.76a) | 2.19 (3.15a) | 6.99 |
| NTZ-1471 | 287.27 | 8.82 | Stable | 46.92 | 92.81 | 4/2 | 0.187 | −3.67 (−4.81a) | n.d. (2.64a) | 6.18 |
| SEL | 187.29 | 8.18 | – | 3.24 | 107.88 | 4/1 | 0.570 | n.d. (−4.10a) | n.d. (2.35a) | 5.83 |
| SAF | 302.35 | 8.29 | – | 64.68 | 86.67 | 4/1 | −0.083 | n.d. (−4.06a) | n.d. (2.89a) | 5.40 |
| b,cCNS+ | ≤400 | >8 | – | <70 | ≥60 | ≤7/≤3 | ≥–1 | ≥ −5.0 | 1–4 | >5 |
MW: molecular weight; pIC50 at human MAO-B; Stability: chemical stability of compounds in 10 mM phosphate buffer at pH 7.4; tPSA: topological surface area (in Å2); %ABS: % of absorption = 109–0.345×tPSA (Ref.29); HBA/D: number of hydrogen bond acceptors/donors; logBB: blood-brain partition coefficient (lit. 31); logS: solubility (in mol/L) at pH 7.4 in 60 mM phosphate buffer or pure water at rt; logD: distribution coefficient at pH 7.4 in 60 mM phosphate buffer at rt; LLE: ligand-lipophilicity efficiency = pIC50–logD (Ref.30); n.d.: not determined; SEL: Selegiline; SAF: Safinamide.
Calculated values using the StarDrop module in SeeSAR 5.5, 201718.
Ref.25–27.
CNS+: required ranges for compound penetration to the central nervous system (CNS).