| Description | BX471 (BX 471) is a potent, selective non-peptide CCR1 antagonist. |
| In vitro | BX 471 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. BX 471 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 | BX 471 (4 mg/kg, p.o. or i.v.) is orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 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]. |
| Cell experiments | Briefly, dermal microvascular endothelial cells grown to confluence in Petri dishes are stimulated with IL-1β (10 ng/mL) for 12 h followed by pre-incubation with RANTES (10 nM) for 30 min at 37°C just prior to assay. The plates are assembled as the lower wall in a parallel wall flow chamber and mounted on the stage of an Olympus IMT-2 inverted microscope with ×20 and ×40 phase-contrast objectives. Isolated human blood monocytes are isolated and resuspended at 5×105?cells/mL in assay buffer (HBSS) containing 10 mM?HEPES, pH 7.4 and 0.5% human serum albumin. Shortly before the assay, 1 mM Mg2+?and 1 mM?Ca2+?are added. The cell suspensions are kept in a heating block at 37°C during the assay and perfused into the flow chamber at a rate of 1.5 dyn/cm2?for 5 min. For inhibition experiments, monocytes are preincubated with BX471 at different concentrations (0.1-10 μM) or a Me2SO control for 10 min at 37°C. The number of firmLy adherent cells after 5 min is quantitated in multiple fields (at least five per experiment) by analysis of images recorded with a long integration JVC 3CCD video camera and a JVC SR L 900 E video recorder and are expressed as cells/mm2. The type of adhesion analyzed is restricted to primary,?i.e.?direct interactions of monocytes with endothelium. |
| Target activity | CCR1:1 nM (Ki) |
| Synonyms | BX 471, BX-471, ZK-811752 |
| molecular weight | 434.89 |
| Molecular formula | C21H24ClFN4O3 |
| CAS | 217645-70-0 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| Solubility | DMSO: 100mg/ml（399.4mM）, Sonication is recommended. |
| 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):192000-8. 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. 5. Yang J Y, Zhang J, Lu R, et al. T cell–derived exosomes induced macrophage inflammatory protein‐1α/β drive the trafficking of CD8+ T cells in oral lichen planus[J]. Journal of cellular and molecular medicine. 2020 |
| Citations | 1. Yang J Y, Zhang J, Lu R, et al. T cell–derived exosomes induced macrophage inflammatory protein‐1α/β drive the trafficking of CD8+ T cells in oral lichen planus. Journal of Cellular and Molecular Medicine. 2020 |