BX471 (hydrochloride)

BX471 hydrochloride is a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca ²⁺ mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration .It demonstrats a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors.It is also able to displace ¹²⁵ I-MIP-1α/CCL3 binding to mouse CCR1 in a concentration -dependent manner with a K _i of 215±46 nM. Increasing concentrations of BX471 inhibits the Ca ²⁺ transients induced by MIP-1α/CCL3 in both human and mouse CCR1 with IC ₅₀ of 5.8±1 nM and 198±7 nM, respectively.BX471 hydrochloride(0.1-10 μM) shows a dose-dependent inhibition of RANTES-mediated and shear-resistant adhesion on IL-1β- activated microvascular endothelium in shear flow in isolated blood monocytes.It also inhibits the RANTES-mediated adhesion of T lymphocytes to activated endothelium.

BX471 hydrochloride(4 mg/kg, po or iv) is orally active with a bioavailability of 60% in dogs. Furthermore, BX471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis.It reaches peak plasma levels of 9 μM by around 30 minutes, and this rapidly declines to approximately 0.4 μM after 2 hours. From 4 to 8 hours the drug plasma levels drops to 0.1 μM or lower. Mice treated with 20 mg /kg of BX471 for 10 days shows a reduction of interstitial CD45 positive leukocytes of approximately 55%. It has a borderline significant effect on the number of CCR5-positive CD8 cells in the peripheral blood. It reduces the amount of FSP1-positive cells by 65% in UUO kidneys as compared with vehicle control. Pretreatment witih BX471 hydrochloride reduces macrophage and neutrophil accumulation in kidney after ischemia-reperfusion injury.