Determination of the inhibitory potential of Ro 61-8048, JM6, M2, and M8 hepatic lysates of mouse, rat, or human KMO
| Compound | IC50 | ||
|---|---|---|---|
| Mouse KMO | Rat KMO | Human KMO | |
| nM | |||
| Ro-61-8048a | 90 ± 15 | 22 ± 0.15 | 170 ± 20 |
| Ro-61 8048a (3 mg/ml protein)b | 27,000/12,000 | 8000/8200 | >30,000 |
| JM6a | 20,000 ± 2500 | 7100 ± 250 | 11,000 ± 5800 |
| M2a | 22,000 ± 0 | 11,000 ± 0 | 39,000 ± 5600 |
| M8b | 27,000 ± 0 | 10,000 ± 0 | 17,000 ± 750 |
↵a Mean ± S.D. of values obtained on 3 different days with triplicate determinations per day.
↵b Individual results obtained on 2 different days with triplicate determinations per day. The low-level activity observed for JM6 could have been from the low-level presence of Ro-61-8048 in the JM6, M2, and M8 stocks. All JM6 metabolites synthesized, except for M3, underwent low-level degradation to Ro-61-8048 (Fig. 2B), and it was not possible to determine their biological activity in the absence of Ro-61-8048. However, their structure-activity relationship for activity is not considered favorable.