Table 3. In Vitro Pharmacology, DMPK, and Plasma:Brain Level (PBL) Data for Select mGlu7 PAMs 20e, 21a, 21c, and 23g.
| Property | 20e | 21a | 21c | 23g |
|---|---|---|---|---|
| MW | 418 | 383 | 408 | 417 |
| cLogP | 3.98 | 4.38 | 5.22 | 3.83 |
| TPSA | 61.1 | 51.8 | 52.8 | 55.1 |
| In vitro Pharmacologya | ||||
| Rat Calcium Assay | ||||
| EC50 (μM) | 1.6 | 1.6 | 0.83 | 1.3 |
| pEC50 ± SEM | 5.81 ± 0.1 | 5.80 ± 0.1 | 6.08 ± 0.11 | 5.89 ± 0.13 |
| [%L-AP4 max ± SEM] | 84.8 ± 17.1 | 116.6 ± 12.3 | 82.0 ± 3.6 | 75.7 ± 14.1 |
| Rat GIRK Assay | ||||
| EC50 (μM) | 1.0 | 0.99 | 0.75 | 0.71 |
| pEC50 ± SEM | 5.99 ± 0.1 | 6.00 ± 0.1 | 6.12 ± 0.07 | 6.15 ± 0.14 |
| [%L-AP4 max ± SEM] | 62.2 ± 9.5 | 62.8 ± 3.4 | 54.5 ± 3.8 | 29.5 ± 7.1 |
| DAT (Ki/IC50) μM | >10 | >10 | >10 | >10 |
| In vitro PK parameters | ||||
| Rat CLHEP(mL/min/kg) | 54.0 | 46.9 | 50.7 | 58.6 |
| mouse CLHEP(mL/min/kg), | 75.8 | 84.4 | 76.2 | 76.2 |
| Rat fu(plasma) | 0.03 | 0.01 | 0.005 | 0.01 |
| [Rat fu (brain)] | [0.006] | [0.002] | [0.001] | [0.002] |
| Mouse fu(plasma) | 0.02 | 0.01 | 0.004 | 0.01 |
| [Mouse fu (brain)] | [0.01] | [0.001] | [0.001] | [0.002] |
| Rat PBL (IV, 0.2 mg/kg) | ||||
| Kp | 4.36 | 4.78 | 4.99 | 6.84 |
| Kp,uu | 0.79 | 0.96 | 1.00 | 1.24 |
| Mouse PBL(IP, 10 mg/kg) | ||||
| Kp | ND | 2.74 | ND | ND |
| Kp,uu | ND | 0.23 | ND | ND |
a
ND = not determined.