BX471 ZK-811752 217645-70-0 CAS 217645-70-0 99.9%

BX471 (ZK-811752) is an orally active, potent and selective non-peptide CCR1 antagonist with a Ki of 1 nM, and exhibits 250-fold selectivity for CCR1 over CCR2, CCR5 and CXCR4.

In Vitro

BX471 is a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca²⁺

mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. BX471 demonstrats a

greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors^[1]. BX471 is also able to displace

125I-MIP-1α/CCL3 binding to mouse CCR1 in a concentration-dependent manner with a Ki of 215±46 nM. Increasing

concentrations of BX471 inhibits the Ca²⁺ transients induced by MIP-1α/CCL3 in both human and mouse CCR1 with IC50 of

5.8±1 nM and 198±7 nM, respectively^[2]. BX471 (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. BX471

also inhibits the RANTES-mediated adhesion of T lymphocytes to activated endothelium^[4].

In Vivo

BX471 (4 mg/kg, p.o. or i.v.) 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[1]. BX471 (20 mg/kg, s.c.) 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%. BX471 has a borderline significant effect on the number of CCR5

positive CD8 cells in the peripheral blood. BX471 reduces the amount of FSP1-positive cells by 65% in UUO kidneys as

compared with vehicle control^[2]. Pretreatment witih BX471 reduces macrophage and neutrophil accumulation in kidney

after ischemia-reperfusion injury^[3].

REFERENCES

[1]. Liang M, et al. Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem. 2000 Jun 23;275(25):19000-8.

[2]. Anders HJ, et al. A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J Clin Invest. 2002 Jan;109(2):251-9.

[3]. Furuichi K, et al. Chemokine receptor CCR1 regulates inflammatory cell infiltration after renal ischemia-reperfusion injury. J Immunol. 2008 Dec 15;181(12):8670-6.

[4]. Horuk R, et al. A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection. J Biol Chem. 2001 Feb 9;276(6):4199-204

For Laboratory R&D Use Only.