In vitro activity: BX471 (also known as ZK-811752) is a novel, oral and non-peptide antagonist of CCR1 (CC chemokine receptor-1) with Ki of 1 nM for human CCR1, and it may be useful in the treatment of chronic inflammatory diseases. BX471 exhibits 250-fold selectivity for CCR1 over CCR2, CCR5 and CXCR4. CCR1 is a prime therapeutic target for treating autoimmune diseases. BX 471 demonstrates a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K(i) ranged from 1 nm to 5.5 nm). BX 471 was 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. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis.

Kinase Assay: BX471 (also known as ZK-811752) is a novel, oral and non-peptide antagonist of CCR1 (CC chemokine receptor-1) with Ki of 1 nM for human CCR1, and it may be useful in the treatment of chronic inflammatory diseases. BX471 exhibits 250-fold selectivity for CCR1 over CCR2, CCR5 and CXCR4. CCR1 is a prime therapeutic target for treating autoimmune diseases.

Cell Assay: 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.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.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.