INCB-3284

INCB 3284 is a pentent, selective and orally bioavailable human CCR2 antagonist, inhibiting monocyte chemoattractant protein-1 binding to hCCR2, with an IC ₅₀ of 3.7 nM. INCB 3284 also causes an IC ₅₀ of 4.7 nM in antagonism of chemotaxis activity, an IC ₅₀ of 84 μM in inhibition of the hERG potassium current. However, INCB 3284 has no effec on CCR1, CCR3, CCR5, CXCR3, and CXCR5, or additional GPCRs at a concentration of 1 μM. Moreover, INCB 3284 potently inhibits CCR2-mediated signaling events such as intracellular calcium mobilization and ERK phosphorylation with IC ₅₀ values of 6 and 2.6 nM, respectively.

INCB 3284 (1 mg/kg/day, ip) reduces liver damage, and decreases microglia activation in AOM-treated mice via inhibition on CCR2. INCB 3284 also significantly reduces the pERK1/2 to tERK1/2 ratio, as well as G-protein signaling pathway activity and proinflammatory cytokine production in cortex lysates from mice administed with azoxymethane.