Table 4–2.
In vitro assessment of ADME properties during lead selection and lead optimization. As in mouse liver microsomes, 5F02 and its analogs were characterized by rapid metabolism in human liver microsomes (+ NADPH) and the ester derivatives (5F02, MC-270016, MC-270017, MC-270019 and MC-270021) showed a slight tendency toward being labile to enzymatic hydrolysis in that system (− NADPH). As in the mouse, the amide analog FC-7820 appeared stable to hydrolytic metabolism in human liver microsomes. All analogs tested showed no inhibitory activity against the human metabolic enzyme CYP2C9 at concentrations up to and including 10 uM but moderate inhibitory potency against human CYP3A4 and CYP2D6.
| Compound | Human Liver Microsome Stability | Inhibition hCYP3A4 IC50 (nM) | Inhibition hCYP2D6 IC50 (nM) | Inhibition hCYP2C9 IC50 (nM) | ||
|---|---|---|---|---|---|---|
| +NADPH | −NADPH | |||||
| Clint (μl/min/mg) | % Remaining* | |||||
| 5F02 | 3.4 | 404 | 88% | 3280 | 1580 | > 10000 |
| FC-7220 | 1.6 | 850 | 100% | 1930 | 2370 | > 10000 |
| MC270016 | 1.9 | 721 | 92% | 2980 | 8540 | > 10000 |
| MC270017 | 1.2 | 1200 | 95% | 1700 | 4400 | > 10000 |
| MC270019 | 1.2 | 1150 | 92% | 4670 | 9930 | > 10000 |
| MC270021 | 1.3 | 1070 | 85% | 3920 | 9250 | > 10000 |
*
Percent remaining after 60 minutes.