Table 2. Modification at the 5-Position on the 2-Pyridyla.
| CCR2, IC50 (nM) |
||||||
|---|---|---|---|---|---|---|
| compd | R | bindingb | CTXc | Alexad IC50 (nM) | dofetilidee IC50 (μM) | patch clampf inh. at 10 μM (%) |
| 7 | H | 11 (8) | 52 (8) | >30 (2) | 34 | |
| 12 | methyl | 6.9 (12) | 15 (12) | 24 (2) | 71 | |
| 13 | 3-pyridyl | 9.0 (2) | 5.4 (2) | 30 (2) | ||
| 14 | 4-pyridyl | 5.7 (2) | 2.6 (2) | 13 (2) | ||
| 15 | 5-pyrimidinyl | 10 (2) | 36 (2) | |||
| 16 | 2-pyrazinyl | 6.0 (4) | 3.8 (4) | 6.5 (2) | >30 (2) | 70 |
| 17 | 2-pyrimidinyl | 5.2 (42) | 3.9 (42) | 19 (12) | >30 (2) | 35 |
| 18 | 2-thiazolyl | 6.0 (4) | 1.8 (4) | 67 (2) | >30 (2) | 85 |
| 19 | 2-oxazolyl | 5.6 (4) | 3.4 (4) | 31 (2) | >30 (2) | 72 |
a
Numbers in parentheses represent numbers of determinations. Standard deviations were less than 30% of the measured value.
b
Antagonism of MCP-1 binding to hCCR2.
c
Antagonism of chemotaxis activity.
d
Alexa whole blood activity (see ref (10) for assay protocol).
e
Dofetilide hERG binding activity.
f
Inhibition of hERG potassium current at 10 μM from single determination of patch clamp assay.