BX471

SKU: orb1305576

Description

BX471 is a potent and selective non-peptide antagonist of the CCR1 chemokine receptor. It is a valuable research tool for studying CCR1-mediated pathways in inflammatory and autoimmune diseases, with applications in both in vitro binding assays and in vivo animal models.

Research Area

Immunology & Inflammation, Infectious Disease & Virology, Pharmacology & Drug Discovery

Key Properties

• CAS Number: 217645-70-0
• MW: 434.89
• Purity: 98.00% (May vary between batches)
• Formula: C₂₁H₂₄ClFN₄O₃
• SMILES: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(N)=O
• Target: CCR
• Solubility: DMSO:125 mg/mL (287.43 mM);10% DMSO+40% PEG300+5% Tween 80+45% Saline:4 mg/mL (9.2 mM)

Bioactivity

• Target IC50:
  RANTES-CCR1:2.8 nM (Ki)|MCP-3-CCR1:5.5 nM (Ki)|CCR1:1 nM (Ki)
• In Vivo:
  BX 471, administered orally (p.o.) or intravenously (i.v.) at a dosage of 4 mg/kg, demonstrates an oral bioavailability of 60% in dogs and effectively mitigates symptoms in a rat model of multiple sclerosis, specifically the experimental allergic encephalomyelitis model. When given subcutaneously (s.c.) at 20 mg/kg, BX 471 achieves peak plasma concentrations of 9 μM within approximately 30 minutes, subsequently decreasing to about 0.4 μM after 2 hours and further dropping to 0.1 μM or below from 4 to 8 hours. Treatment with 20 mg/kg BX 471 for 10 days in mice results in a 55% reduction in interstitial CD45 positive leukocytes. Although the effect on CCR5-positive CD8 cells in peripheral blood is marginally significant, BX 471 notably reduces FSP1-positive cells in UUO (unilateral ureteral obstruction) kidney conditions by 65% compared to controls, and pre-treatment with BX 471 significantly diminishes macrophage and neutrophil accumulation in the kidney following ischemia-reperfusion injury.
• 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. 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. 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.
• Cell Research:
  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.

Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

CC chemokine receptor, CCR, BX 471, BX471, BX-471, human CCR1, Inhibitor, inhibit, ZK-811752, ZK811752, ZK 811752

Compound Identifiers

PubChem CID

512282