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A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection.

Jenh CH, Cox MA, Cui L, Reich EP, Sullivan L, Chen SC, Kinsley D, Qian S, Kim SH, Rosenblum S, Kozlowski J, Fine JS, Zavodny PJ, Lundell D - BMC Immunol. (2012)

Bottom Line: SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models.Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.It is efficacious in multiple preclinical disease models.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Respiratory and Immunology, Merck Research Laboratories, Kenilworth, NJ 07033, USA. chungherjenh@yahoo.com.

ABSTRACT

Background: 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. 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.

Results: In 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.

Conclusions: SCH 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.

No MeSH data available.


Related in: MedlinePlus

Combination of IFN-β therapy and CXCR3 inhibition has an additive effect on delaying disease onset and attenuating disease severity in the mouse EAE model. IFN-β was administered at 1700 ng by daily intramuscular injection and SCH 546738 was orally twice daily at 30 mpk. The mouse EAE was conducted as described in Methods. Treatment with either IFN-β or SCH 546738 alone or the combination significantly delayed disease onset and attenuated disease severity (p < 0.05, two-tailed t test) at day 16, 17 and 19.
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Figure 7: Combination of IFN-β therapy and CXCR3 inhibition has an additive effect on delaying disease onset and attenuating disease severity in the mouse EAE model. IFN-β was administered at 1700 ng by daily intramuscular injection and SCH 546738 was orally twice daily at 30 mpk. The mouse EAE was conducted as described in Methods. Treatment with either IFN-β or SCH 546738 alone or the combination significantly delayed disease onset and attenuated disease severity (p < 0.05, two-tailed t test) at day 16, 17 and 19.

Mentions: Experimental autoimmune encephalomyelitis (EAE) is an animal model for human MS and development of disease is dependent on T cell infiltration into the CNS. In the murine model of EAE, SCH 546738 was tested in combination with interferon-β (IFN-β), a current first-line therapeutic for the amelioration of relapsing-remitting MS. C57BL/6 mice were primed by intravenous injection of pertussis toxin on day 0 and day 2. EAE was induced on day 1 by subcutaneous injection of the myelin peptide MOG 35-55 emulsified in CFA in the back of primed mice. Disease progression was monitored by a scoring system as described in Methods. IFN-β administered at 1700 ng by daily intramuscular injection significantly delayed disease onset and attenuated disease severity at peak of disease compared to vehicle treated animals (Figure 7). Similarly, SCH 546738 at 30 mpk orally twice daily delayed disease onset and attenuated disease severity on days 17 and 19 (Figure 7). Combination treatment with SCH 546738 and IFN-β had a significant additive effect in delaying disease onset and attenuating disease severity compared to treatment with either SCH 546738 or IFN-β alone (Figure 7) suggesting that a CXCR3 antagonist may offer substantial 'add-on' efficacy onto existing IFN-β therapy and further delay the occurrence of relapses in MS patients. In addition, EAE was induced in Lewis rats by subcutaneous injections of guinea pig spinal cord emulsified in CFA into one hind paw. SCH 546738 reduced the severity of the disease in a dose-dependent manner as well (data not shown).


A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection.

Jenh CH, Cox MA, Cui L, Reich EP, Sullivan L, Chen SC, Kinsley D, Qian S, Kim SH, Rosenblum S, Kozlowski J, Fine JS, Zavodny PJ, Lundell D - BMC Immunol. (2012)

Combination of IFN-β therapy and CXCR3 inhibition has an additive effect on delaying disease onset and attenuating disease severity in the mouse EAE model. IFN-β was administered at 1700 ng by daily intramuscular injection and SCH 546738 was orally twice daily at 30 mpk. The mouse EAE was conducted as described in Methods. Treatment with either IFN-β or SCH 546738 alone or the combination significantly delayed disease onset and attenuated disease severity (p < 0.05, two-tailed t test) at day 16, 17 and 19.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3298469&req=5

Figure 7: Combination of IFN-β therapy and CXCR3 inhibition has an additive effect on delaying disease onset and attenuating disease severity in the mouse EAE model. IFN-β was administered at 1700 ng by daily intramuscular injection and SCH 546738 was orally twice daily at 30 mpk. The mouse EAE was conducted as described in Methods. Treatment with either IFN-β or SCH 546738 alone or the combination significantly delayed disease onset and attenuated disease severity (p < 0.05, two-tailed t test) at day 16, 17 and 19.
Mentions: Experimental autoimmune encephalomyelitis (EAE) is an animal model for human MS and development of disease is dependent on T cell infiltration into the CNS. In the murine model of EAE, SCH 546738 was tested in combination with interferon-β (IFN-β), a current first-line therapeutic for the amelioration of relapsing-remitting MS. C57BL/6 mice were primed by intravenous injection of pertussis toxin on day 0 and day 2. EAE was induced on day 1 by subcutaneous injection of the myelin peptide MOG 35-55 emulsified in CFA in the back of primed mice. Disease progression was monitored by a scoring system as described in Methods. IFN-β administered at 1700 ng by daily intramuscular injection significantly delayed disease onset and attenuated disease severity at peak of disease compared to vehicle treated animals (Figure 7). Similarly, SCH 546738 at 30 mpk orally twice daily delayed disease onset and attenuated disease severity on days 17 and 19 (Figure 7). Combination treatment with SCH 546738 and IFN-β had a significant additive effect in delaying disease onset and attenuating disease severity compared to treatment with either SCH 546738 or IFN-β alone (Figure 7) suggesting that a CXCR3 antagonist may offer substantial 'add-on' efficacy onto existing IFN-β therapy and further delay the occurrence of relapses in MS patients. In addition, EAE was induced in Lewis rats by subcutaneous injections of guinea pig spinal cord emulsified in CFA into one hind paw. SCH 546738 reduced the severity of the disease in a dose-dependent manner as well (data not shown).

Bottom Line: SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models.Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.It is efficacious in multiple preclinical disease models.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Respiratory and Immunology, Merck Research Laboratories, Kenilworth, NJ 07033, USA. chungherjenh@yahoo.com.

ABSTRACT

Background: 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. 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.

Results: In 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.

Conclusions: SCH 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.

No MeSH data available.


Related in: MedlinePlus