Table 3. Analogs of Compound 27 and 28.
| protein
binding (fu)c |
P450 inhibition
IC50 (μM)d |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| no. | mGlu5 pIC50 (±SEM)a | mGlu5 IC50 (nM)a | % Glu maxa,b | rat | human | 3A4 | 2D6 | 2C9 | 1A2 |
| 27 | 7.97 ± 0.05 | 11 | 1.6 ± 0.1 | 0.106 | 0.120 | >30 | >30 | 12.1 | 1.0 |
| 33 | 7.48 ± 0.04 | 33 | 1.5 ± 0.2 | 0.081 | 0.074 | >30 | >30 | >30 | >30 |
| 34 | 6.60 ± 0.25 | 251 | 1.5 ± 0.1 | ||||||
| 35 | 7.32 ± 0.02 | 48 | 1.3 ± 0.1 | ||||||
| 28 | 8.51 ± 0.04 | 3.1 | 1.2 ± 0.1 | 0.015 | 0.011 | 4.3 | >30 | 5.4 | 0.2 |
| 36 | 8.14 ± 0.27 | 7.2 | 1.0 ± 0.1 | 0.058 | 0.014 | 3.8 | >30 | 21.5 | 0.2 |
| 37 | 6.80 ± 0.11 | 158 | 1.2 ± 0.1 | ||||||
a
Calcium mobilization mGlu5 assay; values are an average of n ≥ 3 independent experiments.
b
Amplitude of response in the presence of 30 μM test compound as a percentage of maximal response (100 μM glutamate); an average of n ≥ 3 independent experiments.
c
fu = fraction unbound; equilibrium dialysis assay.
d
Assayed in pooled HLM in the presence of NADPH with CYP-specific probe substrates