Table 3. New Combinations from Free–Wilson Analysis.
| R1 | R2 | mTOR IC50/nM (pred)a | PI3Ka sel. (pred)b | pAKT S473 cell IC50/nM | HLM Clint mL min–1 kg–1 | CYP IC50/μMc | |
|---|---|---|---|---|---|---|---|
| 15a | A | i | 10 (17) | 980× (380×) | 12 | 6 | 5d |
| 15b | A | ii | 10 (15) | 1000× (380×) | 7 | 7 | 3 |
| 15c | B | i | 12 (25) | 800× (220×) | 18 | 8 | 3 |
| 15d | B | ii | 13 (22) | 740× (220×) | 9 | 7 | 0.8 |
| 15e | C | ii | 7.1 (11) | 1400× (1900×) | 5 | 6 | 1.3 |
a
Predicted mTOR enzyme IC50 value from Free–Wilson analysis.
b
Predicted selectivity based on the ratio of the predicted PI3Ka enzyme IC50 over the predicted mTOR enzyme IC50 as described in ref (10).
c
The CYP IC50 value with the most potent inhibition was 2C8 unless otherwise noted.
d
CYP-2C9.