Table 1.
The effect of changes at the 7-position on OX antagonism incorporating the most active 1-position analogs
| |||||||
|---|---|---|---|---|---|---|---|
| No. | R1 | R2 | Ar | Ke (OX1, nM)b | Ke (OX2, nM)c | OX2/OX1 | clogP |
| 6 | Pr |
|
Ph | 16.1 ± 3.6 | >10,000 | >621 | 6.86 |
| 12a | Pr |
|
Ph | 121 ± 35 | a | >82.6 | 7.29 |
| 12b | Pr |
|
Ph | 28.8 ± 4.4 | a | >347 | 6.98 |
| 12c | Pr |
|
Ph | 141 ± 42 | a | >70.9 | 7.40 |
| 12d | Pr |
|
Ph | 173 ± 5 | >10,000 | >58 | 6.17 |
| 12f | Pr |
|
Ph | 20.6 ± 2.8 | a | >485 | 6.17 |
| 12g | Pr |
|
Ph | 96.4 ± 34 | >10,000 | >104 | 5.96 |
| 15a | CF3CH2 |
|
3-Py | 29.5 ± 2.2 | 1750 ± 230 | 59 | 5.70 |
| 15b | CF3CH2 |
|
3-Py | 20.4 ± 2.9 | 1360 ± 150 | 67 | 5.39 |
| 19a | CF3CH2 |
|
Ph | 884 ± 70d | a | >11 | 4.47 |
| 19b | CF3CH2 |
|
Ph | >10,000d | a | 0 | 4.47 |
| 19c | CF3CH2 |
|
Ph | 1,860 ± 140d | a | >5.4 | 4.47 |
| 25a | MeSO2 |
|
Ph | 43.0 ± 18 | a | >232 | 5.25 |
| 25b | MeSO2 |
|
Ph | 5.24 ± 1.0 | 1,200 ± 360 | 229 | 5.19 |
a
< 50% inhibition at 10 μM final concentration;
b
Values are the mean of at least three independent experiments in duplicate;
c
Values are the mean of at least two independent experiments in duplicate; for compounds with Ke < 100 nM at OX1 at least three independent experiments in duplicate were performed.
d
Compound appeared insurmountable during standard assay procedure, so incubation was increased to 1 hour.