Table 2.
Inhibitory activity of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 18a–d, 19a–d, 25a, 25b, 25d, 27b, and 27d against ALK5 and p38α MAP kinase.
| Compounds | R | X | IC50 (µM) | Selectivity Index c | |
|---|---|---|---|---|---|
| p38α a | ALK5 b | ||||
| 18a | H | S | >10 | 5.75 | >2 |
| 18b | o-F | S | >10 | >10 | |
| 18c | m-F | S | >10 | 5.00 | >2 |
| 18d | m-CN | S | >10 | >10 | |
| 19a | H | S | >10 | 0.57 | >17 |
| 19b | o-F | S | >10 | 0.28 | >35 |
| 19c | m-F | S | >10 | 0.33 | >30 |
| 19d | m-CN | S | >10 | 0.37 | >27 |
| 25a | H | O | >10 | 5.03 | >2 |
| 25b | o-F | O | >10 | 3.66 | >3 |
| 25d | m-CN | O | >10 | 4.12 | >2 |
| 27b | o-F | S | >10 | >10 | |
| 27d | m-CN | S | >10 | 2.26 | >4 |
| 3 (LY-2157299) | 0.49 | 0.12 | 4 | ||
a p38α MAP kinase was expressed in E. coli as untagged human recombinant protein. The enzyme was purified by Ni-NTH–agarose (Qiagen). A proprietary radioisotopic protein kinase assay (33PanQinase® Activity Assay) was performed at ProQinase GmbH (Freiburg, Germany) using ATF2 as a substrate. b ALK5 was expressed in Sf9 insect cells as a human recombinant GST-fusion protein using the vaculovirus expression system. A proprietary radioisotopic protein kinase assay (33PanQinase® Activity Assay) was performed at ProQinase GmbH (Freiburg, Germany), using casein as a substrate. c IC50 of p38α/IC50 of ALK5.