Table 1. Heteroaryl Analogues 3−14.
| IC50 (nM) |
||||||
|---|---|---|---|---|---|---|
| compd | R | MCP-1a,b | CTXa,c | hERG bindingd | patch clamp at 10 μMe (%) | mouse oral AUCf (nM·h) |
| 3 | pyridin-2-yl | 3.2 (10) | 3.2 (8) | >30 | 57 | 2812 |
| 4 | pyridin-3-yl | 2.6 (16) | 3.9 (12) | >30 | 50 | |
| 5 | pyridin-4-yl | 4.3 (2) | 3.0 (2) | >30 | 100 | |
| 6 | pyrimidin-2-yl | 10.3 (10) | 9.3 (9) | >30 | 25 | 1442 |
| 7 | pyrimidin-4-yl | 7.8 (22) | 7.5 (30) | >30 | 7 | 930 |
| 8 | pyrimidin-5-yl | 14 (2) | 20 (2) | |||
| 9 | pyridazin-3-yl | 7.3 (8) | 5.8 (6) | >30 | 155 | |
| 10 | pyridazin-4-yl | 4.9 (4) | 7.2 (2) | >30 | 80 | |
| 11 | pyrazin-2-yl | 10.9 (22) | 10.4 (30) | >30 | 7 | 1550 |
| 12 | 6-Me-pyridin-3-yl | 2.4 (2) | 5.6 (2) | >30 | 127 | |
| 13 | 6-MeO-pyridin-3-yl | 3.7 (30) | 4.7 (30) | >30 | 7.7 | 617 |
| 14 | 6-EtO-pyridin-3-yl | 3.2 (10) | 2.7 (6) | >30 | 287 | |
a
Averaged values were given from numbers of determinations indicated in parentheses. Standard deviations are within 30% of the measured value. For assay protocols, see ref (10).
b
Antagonism of MCP-1 binding to hCCR2.
c
Antagonism of chemotaxis activity.
d
Dofetilide hERG binding activity from two determinations.
e
Inhibition of hERG potassium current at 10 μM from single determination of patch clamp assay.
f
Normalized mouse oral AUC at 10 mg/kg from cassette studies (three animals each cassette).