Abstract
BackgroundThe CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738.ResultsIn this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.ConclusionsSCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.
Highlights
The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a T helper 1 (Th1) inflammatory response
The IC50 of SCH 546738 is constant (~1 or 2 nM) and independent of the input concentrations of either [125I] hCXCL10 (25-500 pM) or [125I]hCXCL11 (12.5-250 pM) (Figure 2), respectively. These results indicate that SCH 546738 is a non-competitive antagonist of both CXCL10 and CXCL11 binding to CXCR3, suggesting that SCH 546738 binds to CXCR3 receptor at an allosteric site and change its conformation which prevents the binding of both CXCL10 and CXCL11
Competition binding studies show that SCH 546738 is able to displace radiolabeled CXCL10 and CXCL11 from human CXCR3 with high affinity (IC50 ranged from 0.8 to 2.2 nM) in a non-competitive manner
Summary
The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. CXCR3 is a seven-transmembrane G-protein coupled chemokine receptor which has been demonstrated to play an important role in a variety of inflammatory and immunological responses. The marked upregulation of CXCR3 ligand expression and the predominant expression of CXCR3 on infiltrating T cells during allograft rejection in human and in animal models indicate a critical role for CXCR3-dependent T cell recruitment in transplant rejection [11,12,13]. The upregulation of CXCR3 ligands and the increased number of CXCR3+ lymphocytes documented in chronic inflammatory diseases such as rheumatoid arthritis (RA) [14,15,16,17], multiple sclerosis (MS) [18,19] and psoriasis [20] indicates the potential importance of CXCR3-mediated leukocyte recruitment in the pathology of these conditions, and suggests the potential utility of the selective CXCR3 antagonist in the treatment and amelioration of these disorders
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