BX471 HCl is a potent, selective non-peptide CCR1 antagonist (Ki = 1 nM for human CCR1) and exhibits 250-fold selectivity for CCR1 over CCR2, CCR5 and CXCR4.
The CC chemokine receptor 1 (CCR1) is a therapeutic target for the treatment of autoimmune diseases. BX471 HCl is a non-peptide CCR1 antagonist that displaces the CCR1 ligands, including MIP-1α, RANTES, and MCP-3, with high affinity (Ki = 1.0, 2.8, and 5.5 nM, respectively). It also dose-dependently inhibited Ca2+ mobilization induced by MIP-1α (30 nM), RANTES (300 nM), and MCP-3 (100 nM) with IC50 values of 5, 2, and 6 nM, respectively. The increase in the intracellular Ca2+ concentration by 30 nM MIP-1α was completed inhibited by BX471 HCl at a dosage of 300 nM. BX471 HCl at 1 μM inhibited MIP-1α-induced upregulation of CD11b in human blood[3]. The treatment with 20 mg/kg BX471 HCl for 10 days resulted in 55% reduction of interstitial CD45 positive leukocytes in a mouse model of unilateral ureter obstruction (UUO). BX471 HCl-treated mice also showed significantly decreased CCR5-positive CD8 T cells in UUO kidneys as compared with the vehicle controls (44.2% vs. 64.3%). Additionally, BX471 HCl reduced the amount of FSP1-positive cells by 65% in UUO kidneys compared with the vehicle-treated group[4].
作用机制
BX 471 is a potent inhibitor of chemokine binding to CCR. It blocks CCR1 activation as depicted by the inhibition of Ca2+ mobilization, CD11b expression, extracellular acidification and cell migration[3].
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