Table 3.
In-vitro biological evaluation of compounds derived by Scheme 2
| IC50 (nM)* | Microsome stability (min) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Compd. | R | MMP-13 | MMP-2 | MMP-8 | clogD7.4a | clogPb | rat | mouse | human | Collagen cleavage (20 μM) |
| 2 |  |
2.7±0.6 | >5000 | >5000 | 4.2 | 3.0 | 9 | 20 | 12 | >90% |
| 25 |  |
257±35.0 | >5000 | >5000 | 4.2 | 3.0 | 8 | 11 | 6 | <40% |
| 26 |  |
4.4±1.5 | >5000 | >5000 | 5.2 | 4.2 | 4 | 22 | 7 | >90% |
| 27 |  |
159±59.0 | >5000 | >5000 | 5.2 | 4.2 | nd | nd | nd | >90% |
| 28 |  |
2.4±0.1 | 128±23.0 | 17±1.9 | 4.5 | 3.4 | nd | nd | 8 | >90% |
| 29 |  |
289±24.0 | nd | nd | 4.5 | 3.4 | nd | nd | nd | >90% |
| 30 |  |
1.9±0.3 | 936±190 | 113±23.0 | 3.5 | 1.8 | 4 | 52 | 29 | >90% |
| 31 |  |
8.5±1.4 | >5000 | 832±53.0 | 3.9 | 2.5 | 13 | 31 | 74 | >90% |
| 32 |  |
2.5±0.5 | 584±21.0 | 128±47.0 | 3.1 | 1.8 | 15 | 33 | 59 | >90% |
| 33 |  |
43.2±4.8 | >5000 | >5000 | 4.8 | 3.7 | nd | nd | nd | <10% |
*
The IC50 values for MMP-1, MMP-9, and MT1-MMP are >5 μM for all compounds. nd = not determined.
a
Calculated with Pipeline Pilot workflow application (Accelrys) at pH 7.4.
b
Calculated with ChemDraw.