Table 2.
Inhibition potency, selectivity profile, and stability in rat, mouse, and human liver microsomes of compounds derived from Scheme 1.
| IC50 (nM)* | Microsome stability (min) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Compd. | R1 | R2 | X | MMP-13 | MMP-2 | MMP-8 | clogD7.4a | clogPb | rat | mouse | human |
| 2 | Me |  |
F | 2.7±0.6 | >5000 | >5000 | 4.2 | 3.0 | 9 | 20 | 12 |
| 9 |  |
 |
H | 12.9±1. 1 | 500±100 | 140±25.0 | 2.2 | 2.6 | 61 | 39 | >120 |
| 10 |  |
 |
H | 14.4±1.7 | 362±82.0 | >5000 | 2.2 | 2.6 | nd | nd | nd |
| 11 |  |
 |
H | 7.1±0.6 | 172±23.0 | 83±26.0 | 2.97 | 2.6 | 45 | >120 | >120 |
| 12 |  |
 |
H | 6.9±1.2 | 232±32.0 | 117±51.0 | 2.97 | 2.6 | nd | nd | nd |
| 13 |  |
 |
H | 5.5±0.6 | 114± 18.0 | 38±19.0 | 2.92 | 2.6 | nd | nd | nd |
| 14 |  |
 |
H | 6.4±0.9 | 219±28.0 | 110±46.0 | 2.97 | 2.6 | 42 | >120 | >120 |
| 15 |  |
 |
H | 7.3±0.8 | 187±38.0 | 35±16.0 | 3.5 | 2.8 | 19 | 65 | 64 |
| 16 |  |
 |
H | 7.8±1.0 | 189±36.0 | 29±13.0 | 3.5 | 2.8 | nd | nd | nd |
| 17 |  |
 |
F | 9.1±0.4 | > 5000 | 1600±470 | 4.7 | 3.6 | 9 | 38 | 18 |
| 18 |  |
 |
H | 1.6±0.6 | > 5000 | > 5000 | 4.9 | 3.9 | 34 | 26 | 14 |
| 19 |  |
 |
H | > 5000 | nd | nd | 4.9 | 3.9 | nd | nd | nd |
| 20 |  |
 |
F | > 5000 | nd | nd | 5.1 | 4.1 | nd | nd | nd |
| 21 |  |
 |
F | 5.1±0.3 | > 5000 | > 5000 | 5.1 | 4.1 | 42 | 22 | 13 |
| 22 |  |
 |
F | 4.4±1.0 | > 5000 | > 5000 | 3.9 | 3.6 | 29 | 9 | 27 |
| 23 |  |
 |
F | 20±1.2 | >5000 | >5000 | 2.4 | 3.6 | 25 | >120 | >120 |
*
The IC50 values for MMP-1, MMP-9 and MT1-MMP for all compounds are > 5 μM. nd = not determined.
a
Calculated with Pipeline Pilot workflow application (Accelrys) at pH 7.4.
b
Calculated with ChemDraw.