BX 471

Ki: 1 nM to 5.5 nM

The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. BX 471 is a potent, selective, and orally active antagonist of the CC Chemokine Receptor-1.

In vitro: Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1a, RANTES, and monocyte chemotactic protein-3 with high affinity. BX 471 was a potent functional antagonist based on its ability to inhibit plenty of CCR1-mediated effects. BX 471 also demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors [1].

In vivo: Pharmacokinetic studies demonstrated that BX 471 was orally active with a 60% bioavailability in dogs. Furthermore, in a rat experimental allergic encephalomyelitis model of multiple sclerosis, BX 471 effectively reduces disease [1].

Clinical trial: Up to now, BX 471 is still in the preclinical development stage.

Reference:
[1] Liang M, Mallari C, Rosser M, Ng HP, May K, Monahan S, Bauman JG, Islam I, Ghannam A, Buckman B, Shaw K, Wei GP, Xu W, Zhao Z, Ho E, Shen J, Oanh H, Subramanyam B, Vergona R, Taub D, Dunning L, Harvey S, Snider RM, Hesselgesser J, Morrissey MM, Perez HD.  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.

BX-471 Berlex.[Pubmed:12137405]

Curr Opin Investig Drugs. 2002 Jun;3(6):865-9.

Berlex and its parent company, Schering AG, are developing BX-471 (also known as ZK-811752), the lead in a series of non-peptide chemokine receptor 1 (CCR1) antagonists, for the potential treatment of autoimmune diseases, in particular multiple sclerosis (MS) [291682], [376290], [411184]. In March 2000, BX-471 was undergoing phase I trials for the potential treatment of autoimmune diseases [362022]; phase I trials in MS were ongoing in March 2002 [441989], [443941]. Positive results from these trials have been reported and Berlex was planning phase II trials in MS patients as of mid-March 2002 [444906]. In July 2001, Schering estimated filing in the US and EU in 2008 [411184], [416493]. WO-09856771 claims piperazinyl derivatives, pharmaceutical compositions comprising them and their use in the treatment of inflammatory conditions.

Predictions of CCR1 chemokine receptor structure and BX 471 antagonist binding followed by experimental validation.[Pubmed:16837468]

J Biol Chem. 2006 Sep 15;281(37):27613-20.

A major challenge in the application of structure-based drug design methods to proteins belonging to the superfamily of G protein-coupled receptors (GPCRs) is the paucity of structural information (1). The 19 chemokine receptors, belonging to the Class A family of GPCRs, are important drug targets not only for autoimmune diseases like multiple sclerosis but also for the blockade of human immunodeficiency virus type 1 entry (2). Using the MembStruk computational method (3), we predicted the three-dimensional structure of the human CCR1 receptor. In addition, we predicted the binding site of the small molecule CCR1 antagonist BX 471, which is currently in Phase II clinical trials (4). Based on the predicted antagonist binding site we designed 17 point mutants of CCR1 to validate the predictions. Subsequent competitive ligand binding and chemotaxis experiments with these mutants gave an excellent correlation to these predictions. In particular, we find that Tyr-113 and Tyr-114 on transmembrane domain 3 and Ile-259 on transmembrane 6 contribute significantly to the binding of BX 471. Finally, we used the predicted and validated structure of CCR1 in a virtual screening validation of the Maybridge data base, seeded with selective CCR1 antagonists. The screen identified 63% of CCR1 antagonists in the top 5% of the hits. Our results indicate that rational drug design for GPCR targets is a feasible approach.

Chemokine receptor CCR1 regulates inflammatory cell infiltration after renal ischemia-reperfusion injury.[Pubmed:19050287]

J Immunol. 2008 Dec 15;181(12):8670-6.

Neutrophils and macrophages rapidly infiltrate the kidney after renal ischemia-reperfusion injury, however specific molecular recruitment mechanisms have not been fully delineated for these cell types. Here we provide genetic and pharmacologic evidence supporting a positive role for the chemokine receptor CCR1 in macrophage and neutrophil infiltration in a 7 day mouse model of renal ischemia-reperfusion injury. By day 7, injured kidneys from mice lacking CCR1 contained 35% fewer neutrophils and 45% fewer macrophages than injured kidneys from wild-type control mice. Pretreatment of wild-type mice with the specific CCR1 antagonist BX471 also suppressed neutrophil and macrophage infiltration in the model. Injured kidneys from mice lacking CCR1 also had reduced content of the CCR1 ligands CCL3 (MIP-1alpha) and CCL5 (RANTES) compared with injured kidneys from wild-type controls, suggesting a leukocyte source for these inflammatory chemokines and existence of a CCR1-dependent positive feedback loop for leukocyte infiltration in the model. Local leukocyte proliferation and apoptosis were detected after injury, but were not dependent on CCR1. Also, the extent of necrotic and fibrotic damage and decline in renal function in injured kidneys was similar in wild-type and CCR1-deficient mice. Thus, CCR1 appears to regulate trafficking of macrophages and neutrophils to kidney in a mouse model of renal ischemia-reperfusion injury, however this activity does not appear to affect tissue injury.

A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation.[Pubmed:11805137]

J Clin Invest. 2002 Jan;109(2):251-9.

The expression of chemokines and their receptors is thought to contribute to leukocyte infiltration and progressive renal fibrosis after unilateral ureter obstruction (UUO). We hypothesized that blocking the chemokine receptor CCR1 using the nonpeptide antagonist BX471 could reduce leukocyte infiltration and renal fibrosis after UUO. UUO kidneys from BX471-treated mice (day 0-10 and day 6-10) revealed a 40-60% reduction of interstitial macrophage and lymphocyte infiltrate compared with controls. Treated mice also showed a marked reduction of CCR1 and CCR5 mRNA levels, and FACS analysis showed a comparable reduction of CD8+/CCR5+ T cells. Markers of renal fibrosis, such as interstitial fibroblasts, interstitial volume, mRNA and protein expression for collagen I, were all significantly reduced by BX471-treatment compared with vehicle controls. By contrast treatment was ineffective when the drug was supplied only from days 0 to 5. In summary, blockade of CCR1 substantially reduces cell accumulation and renal fibrosis after UUO. Most interestingly, late onset of treatment is also effective. We therefore conclude that CCR1 blockade may represent a new therapeutic strategy for reducing cellular infiltration and renal fibrosis as major factors in the progression to end-stage renal failure.

Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1.[Pubmed:10748002]

J Biol Chem. 2000 Jun 23;275(25):19000-8.

The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl ]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471). 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. BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Pharmacokinetic studies demonstrated that BX 471 was 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. This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases.

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.

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